Alkyl derivatives of prostanoic acids and preparation thereof

ABSTRACT

15- And/or 16-alkyl derivatives of 9,15-dioxygenated prost-13-enoic, prosta-4,13-dienoic and prosta-5,13-dienoic acid, lower alkyl esters thereof and homologs thereof, as well as a process for preparing these derivatives are disclosed. The compounds possess hypotensive, antihypertensive, bronchospasmolytic, gastric acid secretion inhibiting, abortifacient, estrus synchronizing and ovulation regulating properties. The compounds also inhibit the aggregation of platelets and promote the disaggregation of aggregated platelets. Methods for their use are also disclosed.

This is a division of application Ser. No. 351,381, filed Apr. 16, 1973,now U.S. Pat. No. 3,917,668.

BACKGROUND OF THE INVENTION

1. Field of Invention

The invention relates to prostaglandin deriatives. More particularly,this invention relates to 9,15-dioxygenated derivatives ofprost-13-enoic, prosta-4,13-dienoic and prosta-5,13-dienoic acids havinglower alkyl substituents, to homologs thereof, to intermediates used intheir preparation and to a process for preparing these compounds.

2. Description of the Prior Art

A prostaglandin (PG) is a naturally occurring C-20 fatty acid. Thenatural prostaglandin molecule contains a cyclopentane nucleus with twoside chains in trans configuration. The fundamental structure is calledprostanoic acid and is conventionally represented as follows: ##SPC1##

The chemistry and pharmacological effects of the prostaglandins havebeen the subject of several recent reviews; for example, see E. W.Horton, Physiol. Rev., 49, 122 (1969), J. F. Bagli in "Annual Reports inMedicinal Chemistry, 1969", C. K. Cain, Ed., Academic Press, New Yorkand London, 1970, p. 170, and J. E. Pike in "Progress in the Chemistryof Organic Natural Products", Vol. 28, W. Herz, et al. Eds., SpringerVerlag, New York, 1970, p. 313.

The pharmacological effects known to be associated with theprostaglandins relate to the reproductive, cardiovascular, respiratory,gastrointestinal and renal systems.

Due to the increasing interest in these natural products a ratherextensive effort has been given recently to the synthesis ofprostaglandins and their analogs. Included among these syntheses areseveral synthetic methods for the preparation of 9,15-dioxygenatedderivatives of prostanoic or prost-13-enoic acid. For example, thesynthesis of the first pharmacologically active 9,15-dioxygenatedprostanoic acid derivative, 9ξ,15ξ-dihydroxyprost-13-enoic acid(11-desoxyprostaglandin F₁) was reported in detail by J. F. Bagli, T.Bogri and R. Deghenghi, Tetrahedron Letters, 465 (1966). A significantsimplification and modification of that process was described by Bagliand Bogri in U.S. Pat. No. 3,455,992, issued July 15, 1969, whereby9ξ,15ξ-dihydroxyprost-13-enoic acid as well as homologs thereof wereobtained, see also Bagli and Bogri, Tetrahedron Letters, 5 (1967).

Further improvements in the synthesis of 9,15-dioxygenated derivativesof prostanoic acid have been described by Bagli and Bogri in TetrahedronLetters, 1639 (1969) and German Offenlegungsschrift No. 1,953,232,published Apr. 30, 1970, and in British Patent Specification No.1,097,533, published Jan. 3, 1968.

Other recent syntheses of 9,15-dioxygenated derivatives are reported inBelgian Pat. No. 766,521, published November 3, 1971, P. Crabbe and A.Guzman, Tetrahedron Letters, 115 (1972), M. P. L. Caton, et al.,Tetrahedron Letters, 773 (1972), C. J. Sih, et al., Tetrahedron Letters,2435 (1972), F. S. Alverez, et al., J. Amer. Chem. Soc., 94, 7823(1972), A. F. Kluge, et al., J. Amer. Chem. Soc., 94, 9256 (1972), andN. A. Abraham, Tetrahedron Letters, 451, 1973.

More recently, Bagli and Bogri have extended the scope of theirprocesses for preparing 9,15-dioxygenated derivatives of prostanoic acidto include the preparation of 9-oxo-15-hydroxy prostanoic acidderivatives having an alkyl substituent at position 15, U.S. Pat. No.3,671,570, issued June 20, 1972. These 15-alkyl derivatives possesshypotensive, antihypertensive, bronchospasmolytic and gastric acidsecretion inhibiting properties, as well as inhibiting the aggregationof platelets and promoting the disaggregation of aggregated platelets.

It is noteworthy that the synthetic 9,15-dioxygenated prostanoic acidderivatives described above possess a number of the biologicalactivities of the natural compounds although they lack the 11-hydroxylof the latter.

In the natural series attention has been focused recently on certain15-methyl and 16,16-dimethyl derivatives.

15-Methyl PGF₂.sub.α and 15-methyl PGE₂ methyl esters have been reportedto interrupt pregnancy in the rhesus monkey and in the human, K. T.Kirton et al., Ann. N.Y. Acad. Sci., 180, 445(1971). Furthermore,15(R)-methyl and 15(S)-methyl PGE₂ has been reported to inhibit gastricsecretion, see Medical World News, Oct. 20, 1972, p. 70M. Likewise,16,16-dimethyl PGE₂ methyl ester has been described as effective ininhibiting gastric acid secretion, Chemistry, and Engineering News, Oct.16, 1972, p. 12.

It is worth noting at this point that the natural PGE₁, PGE₂, PGF₁.sub.αand PGF₂.sub.α do have the disadvantage of being relatively unstable,see T. O. Oesterling, et al., J. Pharm. Sci., 61, 1861 (1972). Forexample, it is well known that the 11-hydroxy group of PGE₁ and PGE₂participates readily in dehydration reactions under both basic andacidic conditions, see S. Bergstrom et al., J. Biol. Chem. 238, 3555(1963), E. J. Corey et al., J. Amer. Chem. Soc., 90, 3245 (1968), J. E.Pike et al., J. Org. Chem. 34, 3552 (1969) and "The Prostaglandins,Progress in Research", S. M. M. Karim, Ed., Wiley-Interscience, NewYork, 1972, p. 10.

As realized by those skilled in the art this inherent disadvantage ofthe natural compounds must always be taken into account when consideringthe practical aspects of preparation, formulation of storage of thesecompounds. In contrast, the compounds of the present invention are freefrom this disadvantage.

In brief, although 15-alkylated derivatives of both the9,15-dioxygenated derivatives of prostanoic acids, i.e.11-deoxyprostaglandins, and the 15- and 16-alkylated derivatives ofnatural prostaglandins have been described as exhibiting effects on thegastrointestinal system, and although certain methyl esters of the15-alkylated natural derivatives have been described as having effectson the reproductive system, it would appear that the latter effects havenever been associated with 15- and/or 16-alkyl analogs of the9,15-dioxygenated derivatives.

It is the purpose of the present application to disclose the discoveryof certain stable 15-alkylated and/or 16-alkylated derivatives of the9,15-dioxygenated derivatives of prostanoic acid having unexpected highactivity regarding effects on the reproductive system. Morespecifically, the compounds of this invention are effective agents forinducing abortion and for synchronization of estrus and regulation ofovulation in animals.

SUMMARY OF THE INVENTION

The compounds prepared by the process of this invention are representedby formula 1: ##SPC2##

in which m is an integer from zero to two, n is an integer from two tofive, X and Y together represent oxo, or X represents hydroxy and Y ishydrogen, Z represents the radical --(CH₂)₃ --, cis--CH=CH--CH₂ -- orcis-CH₂ --CH=CH--, R¹ is hydrogen or lower alkyl and R², R³ and R⁴ eachare hydrogen or lower alkyl with the provisos that at least one of R²,R³ or R⁴ is lower alkyl and at least one of R² R³ or R⁴ is hydrogen.

Among the preferred compounds of this invention are the compounds offormula 1 in which m is the integer two and n is the integer three.

The compounds of formula 1 are prepared by a process in which thestarting material is the aldehyde of formula L--CHO (2) in which L isthe radical A, B or C: ##SPC3##

wherein R¹ and R⁵ each are lower alkyl, R⁶ is a radical suitable forprotecting a hydroxy group and Z and m are as defined hereinbefore.

Depending on the nature of L of the aldehyde of formula L--CHO, theprocess of this invention is elaborated in the following manner:

In the case where L of the aldehyde of formula L--CHO is radical A, thealdehyde is treated with a Wittig reagent of the formula (AlkO)₂ POCH₂COCR³ R⁴ --(CH₂)_(n) CH₃ in which Alk is an alkyl containing one tothree carbon atoms and R³, R⁴ and n are as defined hereinbefore toobtain the corresponding compound of formula 3

    L--CH=CHCOCR.sup.3 R.sup.4 --(CH.sub.2).sub.n CH.sub.3     3.

in which L, R³, R⁴ and n are as defined hereinbefore; the last-namedcompound of formula 3 is then treated with a metal borohydride or alower alkyl magnesium halide to give the corresponding compound offormula 4 ##STR1## in which L is the radical A as defined herein, R³, R⁴and n are as defined herein, R⁷ is hydrogen and R² is respectivelyhydrogen or lower alkyl; optionally followed by treating the compound offormula 4, so obtained, with a reagent known to be effective forconverting a hydroxy group of known compounds to a protected hydroxygroup, to obtain the corresponding compound of formula 4 in which L isthe said radical A, R², R³, R⁴ and n are as defined herein and R⁷ is aradical suitable for protecting a hydroxy group. -carboxy-(CH.sub.

Thereafter, the instant compound of formula 4 is treated with a malonicester derivative of formula 5 ##STR2## in which R¹ and R⁸ each are loweralkyl and Z and m are as defined herein, in the presence of a basewhereby the compounds of formulae 4 and 5 undergo a base catalyzedcondensation to give the corresponding cyclopentanonetriester of formula6, ##SPC4##

in which m, n, Z, R², R³, R⁴, R⁵ and R⁸ are as defined hereinbefore, R¹is lower alkyl and R⁷ is hydrogen or a radical suitable for protecting ahydroxy group; followed, when R⁷ is a radical suitable for protecting ahydroxy group, by treating the last-named cyclopentanonetriester offormula 6 with an agent known to be effective for removing saidprotecting group to obtain the corresponding compound of formula 6 inwhich R⁷ is hydrogen.

The instant compound of formula 6 is now treated with a base in thepresence of water to give the corresponding keto compound of formula 1in which m, n, Z, R², R³ and R⁴, are as defined herein, X and Y togetherare oxo and R¹ is hydrogen: thereafter, and if desired, the last-namedcompound is treated with a lower alkanol containing one to three carbonatoms in the presence of an acid catalyst to obtain the correspondingester derivative of formula 1 in which m, n, Z, R², R³ and R⁴ are asdefined herein, X and Y together are oxo and R¹ is lower alkyl.

Alternatively, in the case where L of the aldehyde of formula L--CHO isradical B, the aldehyde is treated with the above Wittig reagent offormula (AlkO)₂ POCH₂ COCR³ R⁴ --(CH₂)_(n) CH₃ in which Alk is an alkylcontaining one to three carbon atoms and R³, R⁴ and n are as definedhereinbefore, to obtain the corresponding compound of formula 3, notedabove, in which L is the radical B as defined hereinbefore and R³, R⁴and n are as defined hereinbefore.

Thereafter the compound of formula 3 is treated with either a metalborohydride or a lower alkyl magnesium halide to give the correspondingcompound of formula 4, as noted above, in which L is the radical B asdefined herein, R³, R⁴ and n are as defined herein, R⁷ is hydrogen andR² is respectively hydrogen or lower alkyl, followed by subjecting thelatter compound to conditions known to be effective for removing theradical suitable for protecting a hydroxy group of known compounds, togive the corresponding compound of formula 1 in which m, n, Z, R², R³and R⁴ are as defined herein, X is hydroxy, Y is hydrogen and R¹ islower alkyl.

Thereafter, and if desired, the last-named compound of formula 1 inwhich R² is lower alkyl is treated with an oxidizing agent to afford thecorresponding keto compound of formula 1 in which m, n, Z, R³ and R⁴ areas defined hereinbefore, R¹ and R² are lower alkyl and X and Y togetherare oxo.

Again alternatively, in the case where L of the aldehyde of formulaL--CHO is radical C, the aldehyde is treated with a Wittig reagent ofthe formual (AlkO)₂ POCH₂ COCR³ R⁴ --(CH₂)_(n) CH₃ in which Alk is analkyl containing one to three carbon atoms, R³ and R⁴ each are hydrogenor lower alkyl with the proviso that at least one of R³ or R⁴ is loweralkyl and n is as defined hereinbefore, to obtain the correspondingcompound of formula 3 noted above, in which L is the radical C asdefined hereinbefore and R³, R⁴ and n are as defined hereinbefore.

Thereafter, the instant keto compound of formula 3 is converted to acorresponding ketal derivative, viz., the compound of formula 3 in whichL is the radical D: ##SPC5##

in which Z and m are as defined hereinbefore and R¹ is lower alkyl, bytreating said keto compound with ethylene glycol in the presence of anacid catalyst.

The ketal derivative of formula 3 is now treated with a metalborohydride to give the corresponding compound of formula 4, notedabove, in which L is the said radical D, R³, R⁴ and n are as definedherein, R² is hydrogen and R⁷ is hydrogen; followed by treating saidlast-named compound with an acid in the presence of water to obtain thecorresponding compound of formula 1.

Thereafter, if desired, the aforementioned ester compound of formula 1in which R¹ is lower alkyl, obtained by any of elaborations of theprocess noted above, is converted to its corresponding free acid, acompound of formula 1 in which R¹ is hydrogen, by treatment with a basein the presence of water.

Likewise, if desired, the aforementioned keto compound of formula 1 inwhich X and Y together are oxo, obtained by any of the elaborations ofthe process noted above, is treated with a complex borohydride to givethe corresponding compound of formula 1 in which X is hydroxy and Y ishydrogen.

DETAILS OF THE INVENTION

The numbering system applied to the compounds of this invention, as usedhereinafter, refers to the ω-cyclopentyl(lower)alkanoic acid nucleus.

A feature of this invention is that the process described herein leadsto the compounds of formula 1 in which the two side chains are in thetrans configuration characteristic for the natural prostaglandins. Also,like the natural prostaglandins a double bond in the acid side chain ofthe compounds of this invention has the cis configuration and the doublebond in the side chain bearing the hydroxy group has the transconfiguration.

Notwithstanding the preceding considerations the compounds of thisinvention having one or more asymmetric carbon atoms can exist in theform of various stereochemical isomers. More specifically, the compoundsare produced as a mixture of racemates. These mixtures result from theasymmetric centers bearing a hydroxyl group and can be separated intopure racemates at appropriate stages by methods well known in the art,for example, see below. If desired, the racemates can be resolved intoenantiomorphs also by known methods. It is to be understood that suchracemates and enantiomorphs are included within the scope of thisinvention.

Furthermore, it is to be understood that the pictorial representationsused herein illustrating the compounds of this invention, are to beconstrued as including such racemates and enantiomorphs. For example, informula 1 the dotted line joining the acid side chain to thecyclopentane ring and the solid line joining the side chain bearing thehydroxy group are used for the purpose of illustrating the transrelationship of these two side chains and should not be construed aslimiting the compounds to one enantiomorph but rather as including allpossible enantiomorphs having this trans relationship.

Also included within this invention are the pharmaceutically acceptablesalts of the acids of formula 1 in which R¹ is hydrogen. The lattercompounds are transformed in excellent yield into the correspondingpharmaceutically acceptable salts by neutralization of said lattercompounds with the appropriate inorganic or organic base. The relativestability of the acid facilitates this transformation. The salts possessthe same activities as the parent acid compounds when administered toanimals and may be utilized in the same manner. Suitable inorganic basesto form these salts include, for example, the hydroxides, carbonates,bicarbonates or alkoxides of the alkali metals or alkaline earth metals,for example, sodium, potassium, magnesium, calcium and the like.Suitable organic bases include the following amines: lower mono-, di-and trialkylamines, the alkyl radicals of which contain up to 3 carbonatoms, such as methylamine, dimethylamine, trimethylamine, ethylamine,di- and triethylamine, methylethylamine, and the like; mono-, di- andtrialkanolamines, the alkanol radicals of which contain up to 3 carbonatoms, such as mono, di- and triethanolamine; alkylene-diamines whichcontain up to 6 carbon atoms, such as hexamethylenediamine; cyclicsaturated or unsaturated bases containing up to 6 carbon atoms, such aspyrrolidine, piperidine, morpholine, piperazine and their N-alkyl andN-hydroxyalkyl derivatives, such as N-methyl-morpholine andN-(2-hydroxyethyl)-piperidine, as well as pyridine. Furthermore, theremay be mentioned the corresponding quaternary salts, such as thetetraalkyl (for example tetramethyl), alkyl-alkanol (for examplemethyl-triethanol and trimethyl-monoethanol) and cyclic ammonium salts,for example the N-methyl-pyridinium,N-methyl-N-(2-hydroxyethyl)-pyrrolidinium, N,N-dimethylmorpholinium,N-methyl-N-(2-hydroxyethyl)-morpholinium, N,N-dimethyl-piperidinium andN-methyl-N-(2-hydroxyethyl)piperidinium salts, which are characterizedby an especially good water-solubility. In principle, however, there canbe used all ammonium salts which are physiologically compatible.

The transformations to the salts can be carried out by a variety ofmethods known in the art. For example, in the case of the inorganicsalts, it is preferred to dissolve the selected acid in water containingat least an equivalent amount of a hydroxide, carbonate, or bicarbonatecorresponding to the inorganic salt desired. Advantageously, thereaction is performed in an inert organic solvent, for example,methanol, ethanol, dioxane, and the like. For example, such use ofsodium hydroxide, sodium carbonate or sodium bicarbonate gives asolution of the sodium salt. Evaporation of the water or addition of awater-miscible solvent of moderate polarity, for example, a loweralkanol or a lower alkanone gives the solid inorganic salt if that formis desired.

To produce an amine salt, the selected acid is dissolved in a suitablesolvent of either moderate or lower polarity, for example, ethanol,acetone, ethyl acetate, diethyl ether and benzene. At least anequivalent amount of the amine corresponding to the desired cation isthen added to that solution. If the resulting salt does not precipitate,it can usually be obtained in solid form by addition of a misciblediluent of low polarity, for example, benzene or diethyl ether or byevaporation. If the amine is relatively volatile, any excess can easilybe removed by evaporation. It is preferred to use equivalent amounts ofthe less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe selected acid with an equivalent amount of the correspondingquaternary ammonium hydroxide in water solution, followed by evaporationof the water.

The term "lower alkyl" as used herein contemplates straight chain alkylgroups containing from one to three carbon atoms and includes methyl,ethyl and propyl.

The term "complex borohydride" as used herein contemplates the metalborohydrides, including sodium borohydride, potassium borohydride,lithium borohydride, zinc borohydride and the like, and metaltrihydrocarbylborohydrides including lithium9-alkyl-9-borabicyclo[3,3,1]-nonylhydride, in which the alkyl containsone to seven carbon atoms, preferably lithium9-tert-butyl-9-borabicyclo[3,3,1]nonylhydride, prepared according to theprocedure described in German Offenlegungsschrift 2,207,987, publishedAug. 31, 1972, lithium diisopinocamphenyl-tertbutylborohydride andlithium 2-thexyl-4,8-dimethyl-2-borobicyclo[3,3,1]nonylhydride,described by E. J. Corey et al., J. Amer. Chem. Soc., 93, 1491 (1971),lithium perhydro-9b-borophenalylhydride, described by H. C. Brown and W.C. Dickason, J. Amer. Chem. Soc., 92, 709 (1970) and the like.

The compounds of formula 1 possess interesting pharmacologicalproperties when tested in standard pharmacological tests. In particular,they have been found to possess hypotensive, antihypertensive,bronchospasmolytic, gastric acid secretion inhibiting, abortifacient andestrus synchronizing and ovulation regulating properties, which makethem useful in the treatment of conditions associated with high bloodpressure, in the treatment of asthmatic conditions, in the treatment ofpathological conditions associated with excessive secretion of gastricacid such as, for example, peptic ulcer, in population control, and inanimal husbandry. In addition, the compound of this invention inhibitthe aggregation of platelets and promote the disaggregation ofaggregated platelets, and are useful as agents for the prevention andtreatment of thrombosis.

More particularly, these compounds, when tested in a modification of thetests for determining hypotensive activities described in "ScreeningMethods in Pharmacology", Academic Press, New York and London 1965, page146, using the cat in urethane-chloralose anaesthesia as the test animaland measuring mean arterial blood pressure before and after intravenousadministration of the compounds, have exhibited utility as hypotensiveagents. When tested in the renal hypertensive rat, prepared by themethod of A. Grollman described in Proc. Soc. Exp. Biol. Med., 7, 102(1954), and measuring blood pressure by the method described by H.Kersten, J. Lab. Clin. Med., 32, 1090 (1947), they have exhibitedutility as antihypertensive agents.

Moreover, the compounds of this invention, when tested in a modificationof the test method described by A. K. Armitage, et al., Brit. J.Pharmacol., 16, 59 (1961), have been found to alleviate bronchospasms,and are useful as bronchospasmolytic agents.

Furthermore, the compounds of this invention, when administered to ratsin the test method described by H. Shay, et al., Gastroenterol., 26, 906(1954), have been found to inhibit the secretion of gastric acid, andare useful as agents inhibiting the secretion of gastric acid.

In addition, the compounds of this invention, when tested in amodification of the test method described by G.V.R. Born, Nature, 194,927 (1962), using the aggregometer manufactured by Bryston ManufacturingLimited, Rexdale, Ontario, Canada, have been shown to inhibit theaggregation of platelets and to promote the disaggregation of aggregatedplatelets, and are useful as agents for the prevention and treatment ofthrombosis.

When the compounds of this invention are employed as hypotensive oranti-hypertensive agents, as agents inhibiting gastric acid secretion inwarm-blooded animals, for example, in cats or rats, as agents for theprevention or treatment of thrombosis, or as bronchospasmolytic agents,alone or in combination with pharmacologically acceptable carriers,their proportions are determined by their solutilities, by the chosenroute of administration, and by standard biological practice. Thecompounds of this invention may be administered orally in solid formcontaining such excipients as starch, lactose, sucrose, certain types ofclay, and flavouring and coating agents. However, they are preferablyadministered parenterally in the form of sterile solutions thereof whichmay also contain other solutes, for example, sufficient sodium chlorideor glucose to make the solution isotonic. For use as bronchospasmolyticagents, the compounds of this invention are preferably administered asaerosols.

The dosage of the present hypotensive, antihypertensive, gastric acidsecretion inhibiting, or bronchospasmolytic agents, or agents for theprevention and treatment of thrombosis will vary with the forms ofadministration and the particular hosts under treatment. Generally,treatments are initiated with small dosages substantially less than theoptimum doses of the compounds. Thereafter, the dosages are increased bysmall increments until the optimum effects under the circumstances arereached. In general, the compounds of this invention are most desirablyadministered at a concentration level that will generally affordeffective results without causing any harmful or deleterious sideeffects and preferably at a level that is in a range of from about 0.1mg to about 10.0 mg per kilo, although as aforementioned variations willoccur. However, a dosage level that is in the range of from about 0.5 mgto about 5 mg per kilo is most desirably employed in order to achieveeffective results. When administering the compounds of this invention asaerosols the liquid to be nebulized, for example, water, ethyl alcohol,dichlorotetrafluoroethane and dichlorodifluoromethane, containpereferably from 0.005 - 0.05 per cent of the acid, or a non-toxicalkali metal, ammonium or amine salt thereof, or ester of formula 1.

Furthermore, when the compounds of this invention are tested by themethod of A. P. Labhsetwar, Nature, 230, 528 (1971) whereby the compoundis given subcutaneously on a daily basis to mated hamsters on days 4, 5and 6 of pregnancy, thereafter the animals being sacrificed on day 7 ofpregnancy and the number of abortions counted, the compounds are shownto have abortifacient properties.

For example, complete abortion resulted in all animals when thefollowing compounds of formula 1 were tested according to this method atdoses noted below:

trans,cis-7-[2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentyl]-5-heptenoicacid (Example 59), 2.5 mg/kg/day,

trans,cis-7-[2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentyl]-4-heptenoicacid (Example 59) 2.5 mg/kg/day, and

trans,cis-7-[2-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl]-5-heptenoicacid (Example 75), 0.5 mg/kg/day.

The potency of the above unsaturated compounds is Especially noteworthyin light of the fact that the completely saturated 15-methyl analog,2-(3-hydroxy-3-methyloctyl)-5-oxocyclopentaneheptanoic acid, describedin U.S. Pat. No. 3,671,570, cited above, does not cause completeabortion in the above test at doses less than 30 mg/kg/day.

Furthermore, the compounds of this invention are useful for inducinglabor in pregnant animals at or near term. When the compounds of thisinvention are employed as agents for abortion or for inducing labor, thecompounds are infused intravenously at a dose 0.01 to 100 mg/kg perminute until the desired effect is obtained.

Still furthermore, the compounds of formula 1 are useful for thesynchronization of estrus and the regulation of ovulation in animals.

It is often desirable to synchronize estrus in domestic animals, forexample, horses, cattle, sheep, swine or dogs, in order to be able toperform artificial insemination or mating with a male of the desiredgenetic quality under optimum conditions. In the past, this has beendone by administering to the animals an ovulation-inhibiting agent,withdrawing administration of said agent shortly before the date chosenfor mating or artificial insemination, and relying either upon thenatural production of LH and FSH to induce ovulation and to produceestrus or by administering gonadotrophins. However, this procedure wasnot entirely satisfactory because ovulation at a predetermined timeoccured only in a certain proportion of the animals when gonadotrophinswere not used. On the other hand, the high cost of gonadotrophins andside effects encountered in their administration made this methodimpractical. It is now possible to obtain substantially completesynchronization of ovulation and of estrus, by treating the animals in agiven group with the compound of formula 1 before the predeterminedperiod of time for mating or artificial insemination, so as to obtainovulation and estrus within that time interval. The delay in the onsetof ovulation and estrus following administration of the compound of thisinvention varies with the species of animal. For example, in rodentssuch as rats or hamsters ovulation takes place within 18 hours followingadministration of the compound and in the horse ovulation usually takesplace within one week after the compound is given.

More specifically, synchronization of estrus and regulation of ovulationin the horse is achieved by giving the compound of formula 1, eitherrandomly to a group of horses during the life of the corpus luteum(usually day 5 to day 16 of the cycle) or two to three days prior to theexpected onset of estrus. The compound for example, trans,cis-7-[2α-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl]-5-heptenoicacid, is given by intrauterine infusion, subcutaneously orintramuscularly in sterile solutions. A dosage which is in the range offrom about 1 to 100 mg/1000 lb, preferably 5 to 25 mg/1000 lb isemployed and is administered as a single dose or spread over a period of72 hours. Practically speaking it is preferable to give one-half thetotal dose on two consecutive days for the latter form ofadministration. For example, in a group of horses receiving thismedication on the second and third day before expected estrus, estrusfollows within 24 to 48 hours which in turn in followed by ovulationoccuring in the majority of animals, from the fourth to the sixth daythereafter as determined by rectal palpation of the ovaries.

In a control group receiving no medication the occurance of ovulationwas spread rather unevenly over the third to eighth day after the onsetof estrus.

The process of this invention may be illustrated as shown in theaccompanying flow sheet.

With reference to the starting materials required for the above process,the aldehyde of formula L--CHO in which L is radical A wherein R⁵ isethyl has been described by D. T. Warner, J. Org. Chem., 24, 1536(1959). By following the process described therein for the preparationof that aldehyde and using the appropriate di(lower)alkylbromomalonatethe aldehydes of formula L--CHO in which L is radial A wherein R⁵ is alower alkyl other than ethyl are obtained.

The aldehyde of formula L--CHO in which L is the radical B or C isprepared according to the procedure described in the copending U.S.Application Ser. No. 259,896, filed June 5, 1972 now U.S. Pat. No.3,773,795 Briefly, these starting materials are prepared in thefollowing manner (the symbols m and Z in the following description havethe same significance as described hereinbefore): A lower alkyl ester of2-(ω-carboxy-(CH₂)_(m) --Z--CH₂)cyclopent-2-en-1-one, preferably themethyl ester, conveniently prepared by treating a 2-(ω-carboxy-(CH₂)_(m)--Z--CH₂)cyclopent-2-en-1-one (7), see below, with a lower alkanolcontaining from 1-6 carbon atoms, preferably methanol, andp-toluenesulfonic acid, is treated with nitromethane in the presence ofan alkali metal lower alkoxide, preferably sodium methoxide, to yieldthe corresponding lower alkyl ester, preferably the methyl ester, of a2-(ω-carboxy-(CH₂)_(m) --Z--CH₂)-3-nitromethylcyclopentan-1-one. The1-keto group of the latter is reduced with sodium borohydride to yieldthe corresponding lower alkyl ester of 2-(ω-carboxy-(CH₂)_(m)--Z--CH₂)-3-nitromethylcyclopentan-1-ol, preferably the methyl ester.

The latter two compounds, the 3-nitromethylcyclopentan-1-one and the3-nitromethylcyclopentan-1-ol derivatives are converted to theirrespective aci-forms by treatment with a strong base such as an alkalimetal lower alkoxide, preferably sodium methoxide, or an aqueous alkalimetal hydroxide, preferably sodium hydroxide, and the resulting solutionof the alkali metal salt of the corresponding nitronic acid is added toa cold aqueous solution of a mineral acid, preferably dilute sulfuricacid at a temperature in the range between about -10° C and about 25° C,preferably in the vicinity of 0° C. Extraction of the mixture with awater-immiscible solvent, preferably diethyl ether, and evaporation ofthe latter yields respectively the corresponding 3-aldehyde, namely thedesired ketoaldehyde starting material of formula L--CHO in which L isthe radical C and the unprotected hydroxyaldehyde, precursor to thedesired starting material of formula L--CHO in which L is the radical B.The latter precursor is thereafter transformed into the desired startingmaterial of formula L--CHO in which L is the radical B wherein R⁶ is aradical suitable for protecting a hydroxy group, for example,tetrahydropyran-2-yl (THP), trimethylsilyl (TMS), dimethylisopropylsilyl(DMIS) and tert-butyl. Said transformation is effected by treating theprecursor with a reagent known to be effective for converting a hydroxygroup of a known compound to a protected hydroxy group. Such reagentsinclude an excess of dihydropyran and an acid catalyst for example,p-toluenesulfonic acid, hydrogen chloride or sulfuric acid, for the THPgroup, trimethylchlorosilane with hexamethyldisilazane for the TMSgroup, dimethylisopropylchlorosilane anddiisopropyltetramethyldisilazane for the DMIS group or isobutylene forthe tert-butyl group.

The lower alkyl ester of 2-(ω-carboxy-(CH₂)_(m)--Z--CH₂)cyclopent-2-en-1-one (7), noted above, is prepared by thefollowing convenient process; ##SPC6##

in which Z and m are as defined in the first instance and R¹ is loweralkyl.

With reference to the first step of this process 1,3-cyclohexadione (8)is condensed with an appropriate lower alkyl ω-bromoester of formula 9in the presence of an alkali metal alkoxide in a lower alkanol,preferably sodium methoxide in methanol, to give the dione of formula10.

The latter compound is then treated with t-butyl hypochlorite in themanner described by G. Buchi and B. Egger, J. Org. Chem., 36, 2021(1971), to yield the chloro derivative 11. The latter treatment isperformed preferably under a nitrogen atmosphere using dry chloroform asa solvent. Thereafter, the chloro derivative is treated in a hydrocarbonsolvent, preferably toluene, in the presence of an alkali metalcarbonate, preferably sodium carbonate, at temperatures from 100° to150° C from about 5 to 25 hours whereby ring contraction is effected toyield the desired lower alkyl ester of 2-(ω-carboxy-(CH₂)_(m)--Z--CH₂)cyclopent-2-en-1-one (7).

The ω-bromoacids and the lower alkyl ω-bromoesters of formula 9 utilizedfor the preparation of compound 7 are either known, for example,7-bromo-5-heptenoic acid its corresponding ethyl ester and severalhomologs of these compounds are described in Belgian Pat. No. 766,520,published November 3, 1971, or may be prepared by standard methods; forexample, see "Rodd's Chemistry of the Carbon Compounds", S. Coffey, Ed.,Vol. 1c, 2nd Ed., pp. 201 -252 and the copending application, Ser. No.238,650, filed Mar. 27, 1972 now U.S. Pat. No. 3,849,474.

In practising the process of this invention, the aldehyde of formulaL--CHO in which L is the radical A, B or C is used as the startingmaterial. This aldehyde is treated with a Wittig reagent of the formula(AlkO)₂ POCH₂ COCR³ R⁴ (CH₂)_(n) CH₃ in which Alk is an alkyl containingone to three carbon atoms and R³, R⁴ and n are as defined hereinbefore,in the presence of an alkali metal hydride, preferably sodium hydride,and in an aprotic solvent, preferably dimethoxyethane or dimethylformamide. Acidification with an aqueous acid, preferably aqueous aceticacid, extraction with a water-immiscible solvent, preferably diethylether, followed by washing, drying and evaporation of the latter, yieldsthe corresponding compound of formula L--CH=CHCO--CR³ R⁴ --(CH₂)_(n)CH₃.

The requisite Wittig reagents are prepared by the method of E. J. Coreyand G. T. Kwiatkowski, J. Amer. Chem, Soc., 88, 5654 (1966) using theappropriate lower alkyl alkanoate and di(lower)alkylα-lithiomethanephosphonate.

More specifically, the treatment of the aldehyde derivative of formulaL--CHO in which L is the radical A, B or C with the ylid prepared fromthe Wittig reagent is performed in the following manner. A solution ofthe Wittig reagent in about 5 to 10 parts of an aprotic solvent,preferably dimethoxyethane or dimethylformamide, is added slowly under ablanket of nitrogen to a stirred suspension of approximately oneequivalent of an alkali metal hydride, preferably sodium hydride, inapproximately 150 parts of the aprotic solvent and stirring is continuedat room temperature for a period of time of from 10 to 60 minutes,preferably for about 30 minutes. To the resulting solution of thecorresponding ylid, there is slowly added a solution of approximatelythree quarters to one equivalent, preferably about 0.85 equivalent, ofthe aldehyde of formula L--CHO in about 5 to 10 parts, preferably about8 parts of an aprotic solvent, preferably dimethoxyethane. The additionis carried out at 20° to 100° C, preferably 25° to 65° C over a periodof time of from 5 to 60 minutes. Acidification with an aqueous acid,preferably aqueous acetic acid, followed by extraction with awater-immiscible solvent, preferably diethyl ether, washing and dryingof the extracts, evaporation of the solvent, and chromatography of theresidue on silica gel yields the corresponding compound of formula L--CH= CHCOCR³ R⁴ -- (CH₂)_(n) CH₃ (3) in which L is the radical A, B or Cand R³, R⁴ and n are as defined hereinbefore.

Before proceeding furher with the process of this invention it isexpedient, in the case where L of the last-named compound of formula 3represents the radical C, to protect the 1keto group of thecyclopentanone ring of radical C. Said protection is advantageouslyafforded by treatment of the compound of formula 3 in which L is radicalC with ethylene glycol in the presence of an acid catalyst, for example,p-toluenesulfonic acid, hydrogen chloride or sulfuric acid, in an inertsolvent, for example, benzene or tetrahydrofuran. In this manner thecorresponding compound of formula 3 is obtained in which L is theorganic radical D, as defined hereinbefore, having said protected ketogroup.

Also it is worth noting at this point that a convenient alternativemethod has been found for the preparation of the compound of formula 3in which L is the radical A as defined herein and R³, R⁴ and n are asdefined in the first instance. In this latter method, the aldehyde offormula L-CHO in which L is the radical A is treated with a methylketone of formula CH₃ COR⁹ in which R⁹ is CR³ R⁴ --(CH₂)_(n) CH₃ inwhich R³, R⁴ and n are as defined in the first instance, in the presenceof a base, to obtain the corresponding compound of formula 12,

    L--CH=CH--COR.sup.9                                        12,

which in this case is the desired compound of formula 3 in which L isthe radical A and R³, R⁴ and n are as defined in the first instance.

The aforementioned treatment of the aldehyde with the ketone of formulaCH₃ COR⁹ is performed preferably by using an organic base, for example,piperidine, N-methylpiperidine or N,N-dimethylpiperazine, althoughsodium hydride, potassium tert-butoxide, sodium ethoxide and the likeare alternative suitable bases. If desired an inert solvent, forexample, benzene, ether, dioxane or tert-butanol, is employed for thisreaction. Although not critical, it is prudent to use substantiallyequivalent amounts of the aldehyde and the ketone for the reaction.Advantageous temperatures and times for this reaction include atemperature range of from 20° to 100° C, preferably 60° to 80° C. and areaction time from two to 30 hours.

The instant compound of formula 3 in which L is the radical A, B or D isnow converted to the corresponding compound of formula 4 by one of thefollowing two methods depending on R² of the product being hydrogen orlower alkyl.

When it is desired to obtain the compound of formula 4 in which L is theradical A, B or D and R² is hydrogen, then the compound of formula 3 inwhich L is the radical A, B or D is treated with a metal borohydride,for example, lithium borohydride, potassium borohydride, zincborohydride or preferably sodium borohydride, in an inert solvent, forexample, methanol or tetrahydrofuran, to yield the desired compound offormula 4 as a mixture of epimers. The epimers result from theasymmetric center at the carbon to which the secondary alcohol isattached. The mixture of epimers need not be separated at this stage. Inpractice it has been found more convenient to continue the process withthe mixture of epimers and, if desired, to separate the resultingepimers of compounds of formula 1.

When it is desired to obtain the compound of formula 4 in which L is theradical A or B and R² is lower alkyl then the latter compound of formula3 in which L is the radical A or B is treated with a lower alkylmagnesium halide.

The addition of the lower alkyl magnesium halide to the last saidcompound of formula 3 is carried out according to the conditions of theGrignard reaction. Convenient and practical conditions for this additioninclude ether or tetrahydrofuran as the solvent for the reaction, areaction time of from five minutes to six hours and a reactiontemperature of from -80° to 25° C, preferably -70° to -40° C when L ofthe compound of formula 3 is radical A and preferably -20° to 0° C whenL of the compound of formula 3 is radical B.

Alternatively, a convenient method for preparing the compound of formula4 in which L is the radical A, R² is lower alkyl, R³ is hydrogen and R⁴is hydrogen or lower alkyl and R⁷ is hydrogen, comprises treating thealdehyde of formula L--CHO in which L is the radical A with a methylketone of formula CH₃ COR⁹ in which R⁹ is lower alkyl, in the presenceof a base, to obtain the corresponding compound of formula 12,

    L--CH=CH--COR.sup.9                                        12

followed by treating the latter compound with an appropriate lower alkylmagnesium halide in which the alkyl portion is CR³ R⁴ --(CH₂)_(n) CH₃ inwhich R³, R⁴ and n are as defined in the last instance. In this case thetreatment of the aldehyde with the methyl ketone is performed accordingto the same conditions described hereinbefore for preparing the compoundof formula 12 in which R⁹ is CR³ R⁴ --(CH₂)_(n) CH₃. However, in thiscase it is advantageous to dispense altogether with an inert solvent forthe reaction and to use a large excess of the ketone of formula CH₃COR⁹, i.e. 10 to 100 equivalents, preferably 20 to 60 equivalents.

In other words, it is possible to use the compound of formula 12 in twoways to elaborate the side chain bearing the hydroxy group of thecompound of formula 1. In the case where R⁹ of formula 12 is CR³ R⁴--(CH₂)_(n) CH₃, the R⁹ group is the progenitor of part of thehydrocarbon reside of the side chain itself and in the case where R⁹ islower alkyl the R⁹ group is the progenitor of the alkyl substituent onthe side chain occurring when R² of the compound of formula 1 is loweralkyl.

From this point the process of this invention is completed by one of thefollowing three methods depending on L of the compound of formula 4being the radical A, B or D.

In the first method when L of the compound of formula 4 is the radicalA, the cyclopropyl compound of formula 4 is condensed with a malonicester derivative of formula 5,

    CH(COOR.sup.8).sub.2 CH.sub.2 --Z--(CH.sub.2).sub.m COOR.sup.1 5

in which R¹ and R⁸ each are lower alkyl and Z and m are as definedhereinbefore, in the presence of a base. If desired, but not critical,the hydroxy group of the compound of formula 4 may be protected duringthe course of this condensation. Suitably protection is afforded byreacting said last-named compound of formula 4 with the appropriateaforementioned reagent for providing a protected hydroxy group to affordthe corresponding compound fo formula 4 in which R⁷ is a radicalsuitable for protecting a hydroxy group, for example, THP, TMS, DMIS ortert-butyl, see above.

The malonic ester derivative of formula 5, noted above, is prepared bycondensing the appropriate aforementioned lower alkyl ω-bromoester offormula 9, with a dialkylmalonate, in the presence of an alkali metalalkoxide in a lower alkanol. More particularly, the condensation isperformed preferably by adding the dialkylmalonate portionwise to asolution of one equivalent of sodium methoxide in methanol at atemperature of from 10° to 30° C, preferably room temperature. Afterstirring for about 10 to 20 minutes, the reaction mixture is treatedportionwise with one equivalent of the bromoester of formula 9 followedby heating the reaction mixture at reflux temperature for one to twohours. Thereafter, dilution of the mixture with water, extraction with awater-immiscible solvent, preferbly ether, washing and drying of theextract, followed by removal of the solvent gives a residue, which onpurification by distillation under reduced pressure gives the desiredmalonic ester derivative of formula 5.

Alternatively the malonic ester derivative of formula 5 in which Z isCH₂ CH=CH-- is prepared by treating a (2-formylethyl)malonic aciddi(lower)alkyl ester, for example, (2-formylethyl)malonic acid diethylester, D. T. Warner and O. A. Moe, J. Amer. Chem. Soc., 70, 3470 (1948),with a triphenylphosphonium bromide of formula ##SPC7##

in which R¹ and m are as defined hereinbefore in the presence of analkali metal hydride, preferably sodium hydride, in an aprotic solvent,preferably dimethyl sulfoxide or dimethyl formamide, in the same manneras described previously for the treatment of the aldehyde of formulaL--CHO with the Wittig reagent. In this manner the corresponding malonicester derivative of formula CH(COOR⁸)₂ CH₂ CH₂ CH=CH--(CH₂)_(m) COOR¹ inwhich R¹, R⁸ and m are as defined hereinbefore is obtained. When R¹ ofthe latter compound is hydrogen, said latter compound is converted tothe corresponding malonic ester derivative of formula 5 by treatmentwith a lower alkanol, for example, methanol or ethanol, in the presenceof an acid catalyst, for example, p-toluenesulfonic acid, borontrifluoride etherate or dry hydrogen chloride.

The requisite triphenylphosphonium bromide of formula ##SPC8##

are prepared readily by treating the appropriate ω-bromoacid orωbromoester of formula Br CH₂ --(CH₂)_(m) COOR¹ in which m is as definedhereinbefore with triphenylphosphine in an inert solvent, for example,benzene, or acetonitrile, at 20° - 100° C for 12 to 24 hours andcollecting the precipitate.

As noted previously the cyclopropyl compound of formula 4 and themalonic ester derivative of formula 5 are subjected to a base catalyzedcondensation to give the cyclopentanonetriester of formula 6. Thiscondensation is performed in the presence of a suitable base, preferablyan alkali metal alkoxide, for example, sodium methoxide. Other suitablebases include sodium ethoxide, potassium tert-butoxide, and sodiumhydride. More specifically, this condensation is conveniently effectedby heating a mixture of about eqimolar amounts of the compound offormula 4 and the triester 5 at 80° to 150° C, preferably 100° - 140° C,for 30 minutes to six hours, preferably one to three hours. The reactionmixture is then cooled, neutralized with an acid, for example, aceticacid, and extracted with a water-immiscible solvent, for example,diethyl ether. Evaporation of the extract and purification of theresidue by chromatography on silica gel yields thecyclopentanonetriester of formula 6.

Thereafter, in the case where the hydroxy group has been protected by asuitable protecting group, said group is now removed by an agent knownto be effective for removing such a protecting group. In a preferredembodiment the base catalyzed condensation is effected with a compoundof formula 4 in which R⁷ is tetrahydropyran-2-yl and thereafter thetetrahydropyran-2yl protecting group is removed by treating theresulting cyclopentanonetriester of formula 6 (R⁷ =tetrahydropyran-2-yl) with acid, for example, hydrochloric acid, aqueousacetic acid or preferably p-toluenesulfonic acid, in an inert solvent inthe presence of water, preferably methanol-water (9:1). Other agents forremoving the protecting group are discussed hereinafter.

The cyclopentanonetriester 6 is now treated with an alkali metalhydroxide in the presence of water to give the corresponding compound offormula 1 in which m, n, Z, R², R³ and R⁴ are as defined in the firstinstance, X and Y together are oxo and R¹ is hydrogen. Preferably thisreaction is done by heating a mixture of the cyclopentanonetriester withan alkali metal hydroxide, preferably sodium hydroxide or potassiumhydroxide, in the presence of water at reflux temperature of the mixturefor a period of 15 minutes to six hours, preferably about one to threehours. Neutralization of the reaction mixture with acid, for example, 2NHCl, extraction with a water-immiscible solvent, for example, diethylether, and subsequent work up to the extract yields an epimeric mixtureof the said last-named compound of formula 1. If desired the epimers maybe separated at this stage by chromatography on silica gel.

Thereafter, if desired the latter compound is esterified with a loweralkanol containing one to three carbon atoms, for example, methanol,ethanol or propanol, in the presence of a acid, for example, sulfuricacid, hydrochloric acid or preferably perchloric acid, to give thecorresponding ester compound of formula 1 in which m, n, Z, R², R³ andR⁴ are as defined in the first instance, X and Y together are oxo and R¹is lower alkyl. Optionally, this esterification can be effected bytreating said latter compound with an appropriate diazoalkane, forexample, diazomethane, or diazoethane.

The second method, utilized when L of the aforementioned compound offormula 4 is the radical B, proceeds by treating the said compound offormula 4 with an agent known to be effective for removing a radicalsuitable for protecting a hydroxy group. In a preferred embodiment, L ofthe aforementioned compound of formula 4 is the radical B in which R⁶ isthe TMS radical. The TMS radical is removed by treatment with an excessof water-methanol (10:1 ) for 24 hours or with tetrahydrofuran-aceticacid at room temperature for one to two hours. Alternatively, if R⁶ isDMlS, this protecting group is removed by the same conditions used forthe removal of the TMS radical.

In this manner the compound of formula 1 in which m, n, Z, R², R³ and R⁴are as defined in the first instance, X is hydroxy, Y is hydrogen and R¹is lower alkyl is obtained. This compound is obtained thus as a mixtureof epimers with respect to the hydroxy group of the cyclopentane ring.If desired the epimers can be separated readily by chromatography.

Furthermore, if so desired, the latter compounds of formula 1 in whichR² is lower alkyl are treated with an oxidizing agent capable ofconverting a hydroxy function to the corresponding keto function toyield the corresponding compound of formula 1 in which X and Y togetherare oxo. Suitable oxidizing agents include chromium trioxide-pyridinecomplex, chromium trioxide-sulfuric acid in acetone, with the formerbeing preferred.

The third method, utitlized when L of the compound of formula 4 is theradical D and R² is hydrogen proceeds with preferential hydrolysis ofthe ketal. The hydrolysis is effected by treatment with an acid in thepresence of water, in an inert solvent. Suitable conditions for thishydrolysis include the use of p-toluenesulfonic acid or acetic acid at atemperature of from 25° to 100° C using tetrahydrofuran, dioxane,acetone or methanol as the solvent and a reaction period of from threeto 24 hours. Preferably, the hydrolysis is effected usingp-toluenesulfonic acid in tetrahydrofuran or a mixture of water andmethanol at room temperature for 12 to 24 hours.

In this manner the compound of formula 1 in which m, n, Z, R³ and R⁴ areas defined in the first instance, X and Y together are oxo, R¹ is loweralkyl and R² is hydrogen is obtained.

Finally, and if desired any of the aforementioned compounds of formula 1in which X and Y together are oxo and R¹ is lower alkyl are reduced bytreatment with a complex borohydride to give the corresponding compoundof formula 1 in which X is hydroxy and Y is hydrogen.

This reduction is preferably carried out by treating the compound offormula 1 in which X and Y are oxo with sodium borohydride in an inertsolvent, for example, ethanol or tetrahydrofuran at 0° to 30° C from 30minutes to two hours or with lithium9-tert-butyl-9-borobicyclo[3,3,1]nonylhydride in an inert solvent, forexample, tetrahydrofuran, or diglymetetrahydrofuran at -80° to 0° C,preferably -80° to -60° C, for one to two hours. In this instance theresulting compound of formula 1 in which X is hydroxy and Y is hydrogenand R¹ is hydrogen or lower alkyl is obtained as a mixture of epimericC-2 alcohols. This mixture is conveniently separated into its individualC-2 alcohol epimers by chromatography on silica gel.

The following examples illustrate further this invention.

EXAMPLE 1 Dimethyl 3,3-dimethyl-2-oxoheptyl phosphonate [(AlkO)₂ POCH₂COCR³ R⁴ --(CH₂)_(n) CH₃ in which Alk is CH₃, R³ and R⁴ = CH₃ and n = 3]

The title compound is prepared by treating 2,2-dimethylhexanoic acidmethyl ester, S. M. McElvain, et al., J. Amer. Chem Soc., 75, 3987(1953), with dimethyl methyl phosphonate according to the procedure ofE. J. Corey and G. T. Kwiatkowski, J. Amer. Chem. Soc., 88, 5654 (1966).An exemplification of this procedure is as follows:

Dimethy methylphosphonate (14.86 g) is dissolved in dry tetrahydrofuran(THF, 34 ml) under a nitrogen atmosphere. The solution is cooled to -78°C. Butyllithium (7.68 g, 52 ml of 2.3 molar solution, 3 equiv.) is addedvery slowly during one hour. The mixture is stirred at -78° C for 15minutes. A solution of 2,2-dimethylhexanoic acid methyl ester (6.32 g)in dry THF (16 ml) is added to the cold solution over a period of onehour. The mixture is stirred for 30 minutes and then allowed to warm upto room temperature. The reaction mixture is diluted with ether. Dilute(10%) hydrochloric acid (30 ml) is added and the reaction mixture shakenwell. The organic phase is separated and washed several times withwater, dried (MgSO₄) and the solvent removed, The residue is distilledunder reduced pressure to give the title compound, b.p. 110° - 120°C/0.1mm, γ_(max) ^(film) 1700, 1250, 1020 cm⁻ ¹.

Similarly other Wittig reagents of the formula (AlkO)₂ POCH₂ COCR³ R⁴--(CH₂)_(n) CH₃ in which Alk is an alkyl containing one to three carbonatoms, R³ and R⁴ are hydrogen or lower alkyl and n is an integer fromtwo to five are prepared by using the appropriate lower alkyl alkanoateand di(lower)alkyl methanephosphonate. For instance, treatment of2,2-dipropylpentanoic acid methyl ester with dimethyl methylphosphonategives 2-oxo-3,3-dipropylhexyl phosphonate and treatment of2,2-diethyloctanoic acid ethyl ester with diethyl methylphosphonategives 2-oxo-3,3-diethylnonyl phosphonate.

EXAMPLE 2 Dimethyl 2-formylcyclopropane-1,1-dicarboxylate (2: L =radical A in which R⁵ = CH₃)

By following the procedure of D. T. Warner, cited above, used forpreparing diethyl 2-formylcyclopropane-1,1-dicarboxylate from acroleinbut using equivalent amounts of dimethylbromomalonate and methanolinstead of diethylbromomalonate and ethanol, respectively, the titlecompound, nmr (CDCl₃) δ 1.98 (m, 2H), 2.80 (m, 1H), 3.79 (s, 6H), 8.82(d, J = 4 cps, 1H), is obtained.

Likewise the use of dipropylbromomalonate and propanol gives dipropyl2-formylcyclopropane-1,1-dicarboxylate.

EXAMPLE 3 Diethyltrans-2-(4,4-dimethyl-3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate (3:R³ and R⁴ = CH₃, n = 3 and L = radical A in which R⁵ = C₂ H₅)

To a suspension of 50% sodium hydride (0.46 g, washed with hexane) indimethylformamide (DMF) is added a solution of dimethyl3,3-dimethyl-2-oxoheptyl phosphonate (2.75 g), described in Example 1,in DMF (15 ml ) over a period of 30 min. The mixture is stirred andcooled in ice water during the addition and for an additional period of45 min. A solution of diethyl 2-formylcyclopropane-1,1-dicarboxylate(2.14 g) in DMF (15 ml) is added over 20 min. The reaction mixture isheated at 55° to 60° C and stirred for 45 min. The mixture is now cooledin an ice bath and acetic acid is added to render the mixturesubstantially neutral. The reaction mixture is poured into water (4 ×the volume) and the resulting oily precipitate extracted with ether. Theextract is washed with water, dried (Na₂ SO₄) and concentrated. Theresidue is dissolved in ethyl acetate-benzene (1:9) and the solutionpoured through a column of silica gel (148 g). The eluate isconcentrated to yield the title compound, γ_(max) ^(film) 1725, 1680,1620 cm⁻ ¹, nmr (CDCl₃) δ 0.88 (t, 3H), 4.27 (4H), 6.5, 6.68 and 7.39(m, 2H), γ_(max) ^(EtOH) 242 nm (ε = 7500).

In the same manner but replacing diethyl2-formylcyclopropane-1,1-dicarboxylate with dimethyl2-formylcyclopropane-1,1-dicarboxylate, dimethyltrans-(4,4-dimethyl-3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate,γ_(max) ^(film) 1728, 1682 cm⁻ ¹, is obtained.

In the same manner but replacing dimethyl 3,3-dimethyl-2-oxoheptylphosphonate with an equivalent amount of dimethyl 3-methyl-2-oxoheptylphosphonate, b.p. 112° - 115° C/0.2 mm, prepared from 2-methylhexanoicacid methyl ester or the 2 methylhexanoic acid chloride according to theprocedure of Example 1, diethyltrans-2-(4-methyl-3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate,γ_(max) ^(film) 1725, 1680, 1665, 1620 cm ⁻ ¹, nmr (CDCl₃) δ 4.19 (q, J= 7, 4H), 6.32 (d, J = 5, 2H), is obtained.

In the same manner but replacing dimethyl 3,3-dimethyl-2-oxoheptylphosphonate with an equivalent amount of dimethyl 2-oxoheptylphosphonate, described by E. J. Corey, et al., J. Amer. Chem. Soc., 90,3247 (1968), diethyltrans-2-(3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate, b.p. 153° -154° C/0.7 mm, is obtained.

In the same manner but replacing dimethyl3,3-dimethyl-2-oxoheptylphosphonate with an equivalent amount ofdimethyl 3-ethyl-2-oxohexyl phosphonate, dimethyl 3-propyl-2-oxooctylphosphonate, or dimethyl 3-ethyl-2-oxononyl phosphonate, dimethyltrans-2-(4-ethyl-3-oxo-1-heptenyl)cyclopropane-1,1-dicarboxylate,dimethyltrans-2-(3-oxo-4-propyl-1-nonenyl)cyclopropane-1,1-dicarboxylate anddimethyl trans-2-(4-ethyl-3-oxo-1-decenyl)cyclopropane-1,1dicarboxylateare obtained, respectively.

By following the procedure of Example 3 and utilizing the appropriateWittig reagent and the aldehyde of formula L--CHO in which L is theradical A wherein R⁵ is lower alkyl then other compounds of formula 3are obtained. Examples of such compounds of formula 3 are listed inTable I together with the appropriate Wittig reagent and aldehyde offormula L--CHO utilized for their preparation.

                                      TABLE I                                     __________________________________________________________________________    Wittig Reagent      L-CHO    Product: (Prefix Listed                          (AlkO.sub.2)POCH.sub.2 COCR.sup.3 R.sup.4 --(CH.sub.2).sub.n CH.sub.3                             L = radical A                                                                          below)-cyclopropane                              Ex. Alk R.sup.3                                                                            R.sup.4                                                                            n R.sup.5  1,1-dicarboxylate                                __________________________________________________________________________    4   CH.sub.3                                                                          H    H    2 CH.sub.3 dimethyl trans-2-(3-oxo-                                                      1-heptenyl)                                      5   CH.sub.3                                                                          H    H    4 C.sub.2 H.sub.5                                                                        diethyl trans-2-(3-oxo-                                                       1-nonenyl)                                       6   CH.sub.3                                                                          H    H    5 CH.sub.3 dimethyl trans-2-(3-oxo-                                                      1-decenyl)                                       7   CH.sub.3                                                                          CH.sub.3                                                                           H    2 C.sub.2 H.sub.5                                                                        diethyl trans-2-(4-                                                           methyl-3-oxo-1-heptenyl)                         8   CH.sub.3                                                                          CH.sub.3                                                                           H    4 CH.sub.3 dimethyl trans-2-(4-                                                          methyl-3-oxo-1-nonenyl)                          9   CH.sub.3                                                                          C.sub.2 H.sub.5                                                                    H    3 C.sub.2 H.sub.5                                                                        diethyl trans-2-(4-ethyl-                                                     3-oxo-1-octenyl)                                 10  CH.sub.3                                                                          C.sub.2 H.sub.5                                                                    H    5 CH.sub.3 dimethyl trans-2-(4-                                                          ethyl-3-oxo-1-decenyl)                           11  CH.sub.3                                                                          n-C.sub.3 H.sub.7                                                                  H    2 C.sub.2 H.sub.5                                                                        diethyl trans-2-(3-oxo-                                                       4-propyl-1-heptenyl)                             12  CH.sub.3                                                                          n-C.sub.3 H.sub.7                                                                  H    4 CH.sub.3 dimethyl trans-2-(3-oxo-                                                      4-propyl-1-nonenyl)                              13  C.sub.2 H.sub.5                                                                   CH.sub.3                                                                           CH.sub.3                                                                           5 n-C.sub.3 H.sub.7                                                                      dipropyl trans-2-(4,4-                                                        dimethyl-3-oxo-1-decenyl)                        14  C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                    CH.sub.3                                                                           5 n-C.sub.3 H.sub.7                                                                      dipropyl trans-2-(4-ethyl-                                                    4-methyl-3-oxo-1-decenyl)                        15  C.sub.2 H.sub.5                                                                   n-C.sub.3 H.sub.7                                                                  CH.sub.3                                                                           2 CH.sub.3 dimethyl trans-2-(4-                                                          methyl-3-oxo-4-propyl-1-                                                      heptenyl)                                        16  C.sub.2 H.sub.5                                                                   n-C.sub.3 H.sub.7                                                                  n-C.sub.3 H.sub.7                                                                  4 C.sub.2 H.sub.5                                                                        diethyl trans-2-(3-oxo-4,-                                                    4-dipropyl-1-nonenyl)                            __________________________________________________________________________

EXAMPLE 17 Diethyl trans-2-(3-hydroxy-4,4-dimethyl-1-octenyl)cyclopropane- 1,1-dicarboxylate (4; R² and R⁷ = H, R³ and R⁴ = CH₃, n =3 and L = radical A in which R⁵ = C₂ H₅)

Sodium borohydride (0.19 g) is added to a solution of diethyltrans-2-(4,4-dimethyl-3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate(1.62 g), described in Example 3, in ethanol (2.5 ml) at 0° to 5° C.After the addition the mixture is rendered neutral by the addition ofacetic acid, diluted with ether and washed with water. The ether phaseis dried (Na₂ SO₄) and concentrated. The residue is dissolved in ethylacetate-benzene (1:9) and the solution poured through a column of silicagel (50 g). The eluate is concentrated to give the title compound,γ_(max) ^(film) 3500, 1706 cm⁻ ¹, nmr (CDCl₃) δ 2.6 (m, 1H), 3.78 (m,1H), 4.21 (q, 4H), 5.28 (q, 1H), 5.9 (q, 1H).

In the same manner but replacing diethyltrans-2-(4,4-dimethyl-3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylatewith an equivalent amount of diethyl trans-2(4-methyl-3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate, described in Example 3, diethyltrans-2-(3-hydroxy-4-methyl-1-octenyl)cyclopropane-1,1-dicarboxylate,γ_(max) ^(film) 3500 cm⁻ ¹, is obtained.

By following the procedure of Example 17 and utilizing the appropriatecompound of formula 3 then other compounds of formula 4 (R² = H) areprepared. Examples of such compounds of formula 4 are listed in TableII. In each case the compound of formula 3 used as starting material isnoted by the Example in which it is prepared.

                                      TABLE II                                    __________________________________________________________________________                                PRODUCT: (PREFIX LISTED                                 NO. OF EXAMPLE IN WHICH STARTING                                                                    BELOW)-CYCLO-                                     EXAMPLE                                                                             MATERIAL OF FORMULA 3 IS PREPARED                                                                   PROPANE-1,1-DICARBOXYLATE                         __________________________________________________________________________    18    3                     dimethyl trans-2-(4-ethyl-                                                    3-hydroxy-1-heptenyl)                             19    3                     diethyl trans-2-(3-hydroxy-                                                   4-propyl -1-nonenyl)                              20    3                     dimethyl trans-2-(4-ethyl-                                                    3-hydroxy-1-decenyl)                              21    7                     diethyl trans-2-(3-hydroxy-                                                   4-methyl-1-heptenyl)                              22    8                     dimethyl trans-2-(3-hydroxy-                                                  4-methyl-1-nonenyl)                               23    9                     diethyl trans-2-(4-ethyl-3-                                                   hydroxy-1-octenyl)                                24    10                    dimethyl tran-2-(4-ethyl-3-                                                   hydroxy-1-decenyl)                                25    11                    diethyl trans-2-(3-hydroxy-4-                                                 propyl-1-heptenyl)                                26    12                    dimethyl trans-2-(3-hydroxy-                                                  4-propyl-1-nonenyl                                27    13                    dipropyl trans-2-(3-hydroxy-                                                  4,4-dimethyl-1-decenyl)                           28    14                    dipropyl trans-2-(4-ethyl-                                                    3-hydroxy-4-methyl-1-decenyl)                     29    15                    dimethyl trans-2-(3-hydroxy-                                                  4-methyl-4-propyl-1-heptenyl)                     30    16                    diethyl trans-2-(3-hydroxy-4,-                                                4-dipropyl-1-nonenyl)                             __________________________________________________________________________

EXAMPLE 31 Diethyltrans-2-(3-hydroxy-3methyl-1-octenyl)cyclopropane-1,1-dicarboxylate (4;R² = CH₃, R³, R⁴ and R⁷ = H, n = 3 and L = radical A in which R⁵ = C₂H₅)

A solution of the lower alkyl magnesium halide, methyl magnesium iodide,prepared from 24.31 g of magnesium turnings and 157 g of methyl iodidein 1000 ml of ether, is cooled to -70° C. Diethyltrans-2-(3-oxo-1-octenyl)cyclopropane -1,1-dicarboxylate (124.2 g);described in Example 3, in 600 ml ether is added slowly taking care thatreaction mixture temperature does not exceed -45° C. The mixture isstirred 75 min. at the temperature range -50° to -45° C. Aqueoussaturated NH₄ Cl solution is added slowly keeping the temperature of thereaction mixture below -55° C. The mixture is diluted with water andextracted with 1500 ml ether. The ether layer is washed with saturatedNaCl solution twice, then with 10% sodium thiosulfate solution twice,again with saturated NaCl solution, dried (Na₂ SO₄) and concentrated togive a greenish yellow oil. The oil is dissolved in ethylacetate-benzene (3:17) and poured through a column of silical gel. Theeluate is concentrated to yield the title compound, nmr (CDCl₃) δ 0.88(t, J = 5, 3H), 2.45 (q, 2H), 4.13 (q, 2H), 5.14 (2×d, J = 16.8, 1H),5.72 (d, J = 16, 1H).

In the same manner but replacing methyl magnesium iodide with anequivalent amount of ethyl magnesium chloride, or propyl magnesiumbromide, diethyltrans-2-(3-ethyl-3-hydroxy-1-octenyl)-cyclopropane-1,1-dicarboxylate anddiethyltrans-2-(3-hydroxy-3-propyl-1-octenyl)cyclopropane-1,1-dicarboxylate,are obtained, respectively.

In the same manner but replacing diethyltrans-2-(3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate with anequivalent amount of diethyltrans-2-(4-methyl-3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate,described in Example 3 and using methyl magnesium iodide, ethylmagnesium chloride or propyl magnesium bromide as the lower alkylmagnesium halide, diethyltrans-2-(3-hydroxy-3,4-dimethyl-1-octenyl(cyclopropane-1,1-dicarboxylate,diethyltrans-2-(3-ethyl-3-hydroxy-4-methyl-1-octenyl)cyclopropane-1,1-dicarboxylateand diethyltrans-2-(3-hydroxy-4-methyl-3-propyl-1-octenyl)-cyclopropane-1,1-dicarboxylate,are obtained, respectively.

By following the procedure of Example 31 and utilizing the appropriatelower alkyl magnesium halide and compound of formula 3, for examplethose described in Examples 4 to 12, then other compounds of formula 4in which R² is lower alkyl are obtained. Examples of such compounds offormula 4 are listed in Table III together with the requisite loweralkyl magnesium halide and the compound of formula 3.

                                      TABLE III                                   __________________________________________________________________________                                        PRODUCT:                                        NO. OF EXAMPLE                (PREFIX LISTED                                  IN WHICH STARTING MATERIAL                                                                      LOWER ALKYL BELOW)-CYCLOPROPANE-                      EXAMPLE                                                                             OF FORMULA 3 IS PREPARED                                                                        MAGNESIUM HALIDE                                                                          1,1-DICARBOXYLATE                         __________________________________________________________________________    32         4            CH.sub.3 MgI                                                                              dimethyl trans-2-(3-                                                          hydroxy-3-methyl-1-                                                           heptenyl)                                 33         5            C.sub.2 H.sub.5 MgBr                                                                      diethyl trans-2-(3-                                                           ethyl-3-hydroxy-1-                                                            nonenyl)                                  34         6            n-C.sub.3 H.sub.7 MgCl                                                                    dimethyl trans-2-(3-                                                          hydroxy-3-propyl-1-                                                           decenyl)                                  35         7            CH.sub.3 MgBr                                                                             diethyl trans-2-(3-                                                           hydroxy-3,4-dimethyl-                                                         1-heptenyl)                               36         8            C.sub.2 H.sub.5 MgCl                                                                      dimethyl trans-2-(3-                                                          ethyl-3-hydroxy-4-                                                            methyl-1-nonenyl)                         37         9            n-C.sub.3 H.sub.7 MgCl                                                                    diethyl trans-2-(4-                                                           ethyl-3-hydroxy-3-                                                            propyl-1-octenyl)                         38         10           CH.sub.3 MgI                                                                              dimethyl trans-2-(4-                                                          ethyl-3-hydroxy-3-                                                            methyl-1-decenyl)                         39         11           C.sub.2 H.sub.5 MgCl                                                                      diethyl trans-2-(3-                                                           ethyl-3-hydroxy-4-                                                            propyl-1-heptenyl)                        40         12           n-C.sub.3 H.sub.7 MgCl                                                                    dimethyl trans-2-(3-                                                          hydroxy-3,4-dipropyl-                                                         1-nonenyl)                                __________________________________________________________________________

EXAMPLE 41 Diethyltrans-2-{3-[(tetrahydropyran-2-yl)oxy]-3-methyl-1-octenyl}cyclopropane-1,1-dicarboxylate(4, R² = CH₃, R³ and R⁴ = H, R⁷ = (tetrahydropyran-2-yl)oxy, n = 3 and L= radical A in which R⁵ = C₂ H₅)

A solution of diethyltrans-2-(3-hydroxy-3-methyl-1-octenyl(cyclopropane-1,1-dicarboxylate(22.4 g), described in Example 31, dihydropyran (80 ml, distilled oversodium) and p-toluenesulfonic acid monohydrate (300 mg) is allowed tostand at room temperature for 30 min. After added a few ml of 10% Na₂CO₃ solution the mixture is extracted with ether. The ether extract iswashed with water, dried (Na₂ SO₄) and evaporated. Purification of theresidue by chromatography on silica gel gives the title compound, nmr(CDCl₃) δ 0.87 (t, 3H), 2.48 (m, 1H), 4.6 (1H), 5.5 (m, 2H).

In the same manner but using an equivalent amount of one of thecompounds of formula 4 (R⁷ = H), for example, the compounds listed inExamples 17 to 40, instead of diethyltrans-2-(3-hydroxy-3-methyl-1-octenyl)cyclopropane-1,1-dicarboxylate,then the corresponding tetrahydropyranyl ether compound of formula 4 (R⁷= tetrahydropyranyl) is obtained, for example, the correspondingtetrahydropyranyl ether compounds of Example 17 to 40, respectively.More specifically exemplified, in the same manner diethyltrans-2-(3-hydroxy-4-methyl-1-octenyl)-cyclopropane-1,1-dicarboxylate,described in Example 17 gives diethyltrans-2-{3-[(tetrahydropyran-2-yl)oxy]-4-methyl-1-octenyl}-cyclopropane-1,1-dicarboxylate,γ_(max) ^(film) 1035, 1140, 1220 cm⁻ ¹, and dimethyltrans-2-(4-ethyl-3-hydroxy-1-decenyl)cyclopropane-1,1-dicarboxylate,described in Example 24, gives dimethyl trans-2-{4-ethyl-3-[(tetrahydropyran-2-yl)oxy]-1-decenyl}-cyclopropane-1,1-dicarboxylate.

EXAMPLE 42 Trimethyl cis-3-heptene-1,1,7-tricarboxylate (5, R¹ and R⁸ =CH₃, Z = --CH = CHCH₂ -- and m = 2)

Dimethyl malonate (39.6 g) is added slowly with cooling and stirring toa solution of 6.9 g of sodium dissolved in 100 ml of absolute methanoland the mixture stirred for 15 min. The bromoester of formula 9, methylcis-7-bromo-5-heptenoate (65.7 g) is added dropwise. The mixture isheated at reflux for 1 hr., cooled and diluted with water. The mixtureis extracted with ether. The ether extracts are dried (Na₂ SO₄) andconcentrated. The residue is distilled under reduced pressure to givethe title compound, b.p. 140° - 150° C/0.7 mm.

The title compound is also described in copending application Ser. No.238,650, filed Mar. 27, 1972.

In the same manner but replacing methyl cis-7-bromo-5-heptenoate with anequivalent amount of methyl 7-bromo-4-heptenoate, methyl6-bromo-4-hexenoate, methyl 6-bromo-3-hexenoate, methyl5-bromo-3-pentenoate, methyl 5-bromo-2-pentenoate, methyl7-bromoheptanoate, methyl 6-bromohexanoate or methyl 5-bromohexanoate,trimethyl 4-heptene-1,1,7-tricarboxylate, trimethyl3-hexene-1,1,6-tricarboxylate, trimethyl 4-hexene-1,1,6-tricarboxylate,trimethyl 3-pentene-1,1,5-tricarboxylate, trimethyl4-pentene-1,1,5-tricarboxylate, trimethyl heptane-1,1,7-carboxylate,trimethyl hexane-1,1,6-tricarboxylate and trimethylpentane-1,1,5-tricarboxylate are obtained, respectively.

By using the corresponding ethyl or other lower alkyl ester analogs ofthe methyl ester starting materials noted above, the corresponding ethylor other lower alkyl esters of the methyl ester products, noted above,are obtained.

The following example discloses an alternative preparation of the aboveΔ⁴ triesters of formula V.

EXAMPLE 43 Triethyl cis-4-heptene-1,1,7-tricarboxylate (5, R¹ and R⁸ =C₂ H₅, Z =--CH₂ CH=CH-- and m = 2)

For the following reaction, butyric acid triphenylphosphonium bromide,m.p. 245°- 246°C, is prepared by treating γ-bromobutyric acid (100 g)with triphenyl phospine in benzene (630 ml) at reflux temperature for 16hr. and recrystallizing the resulting precipitate from ethanol.

Sodium hydride (50%, 19.46 g) is dissolved in dimethylsulfoxide (404 ml)with warming (70°- 80°C)under a nitrogen atmosphere. The solution iscooled to 15° to 20°C. A solution of butyric acid triphenylphosphoniumbromide (86.99 g) in dimethylsulfoxide is added. The mixture is stirredat the latter temperature for 5 min. and then treated dropwise with(2-formylethyl)malonic acid diethyl ester (39.7 g), described by Warnerand Moe, cited above, over a period of 20 min. The mixture is stirred atroom temperature for 21/2 hr. and then cooled (10°- 20° C) and renderedacidic with acetic acid (60 ml). The reaction mixture (pH = about 6) ispoured into 21/2 litres of ice water. After extraction with either (2×),the aqueous layer is rendered acidic with concentrated hydrochloric acidto pH = 3 and extracted with ether (2×). The ether extracts are combinedand washed with water (2×), then extracted with 10% Na₂ CO₃ solution (3× 200 ml). The aqueous sodium carbonate extracts are washed with ether(2×) and rendered acidic with conc HCl to pH 5. The acidic solution isextracted with ether (2×). The ether extracts are washed with water,dried and concentrated to dryness to give 1,1-diethylcis-4-heptene-1,1,7-tricarboxylate.

The latter compound (21.4 g) in absolute ethanol (214 ml) is heated atreflux with p-toluenesulfonic (0.214 g) for 20 hr. After cooling to roomtemperature the reaction mixture is treated with 4 ml of pyridine andthen diluted with water (750 ml). The mixture is extracted with ether.The ether extrat is washed with water, dried (MgSO₄) and concentrated togive the title compound, γ_(max) ^(film) 1735 cm⁻ ¹.

In the same manner other Δ⁴ -triesters of formula 5, namely triethyl4-hexene-1,1,6-tricarboxylate and triethyl4-pentene-1,1,5-tricarboxylate, are prepared by replacing butyric acidtriphenylphosphonium bromide with propionic acid triphenyl phosphoniumbromide and acetic acid triphenyl phosphonium bromide, respectively.

EXAMPLE 44 Dimethyl cis,trans-3-(6-carbomethoxy-2-hexenyl)-4-(3-hydroxy-4,4-dimethyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate(6, m = 2, n = 3, Z = --CH=CHCH₂ --, R¹ , R³, R⁴, R⁵ and R⁸ = CH₃ and R²and R⁷ = H)

To a solution of trimethyl cis-3-heptene-1,1,7-tricarboxylate (1.36 g),described in Example 42, in 3 ml of methanol, a freshly preparedsolution of sodium methoxide (from 0.126 g of sodium and 6 ml ofabsolute methanol) is added. The mixture is heated to 80°C. A solutionof dimethyltrans-(4,4-dimethyl-3-hydroxy-1-octenyl)cyclopropane-1,1-dicarboxylate(1.7 g) is gradually added to the mixture and the resulting mixturestirred for an additional 15 min. The methanol is removed bydistillation at reduced pressure. The reside is then heated at 100°C for45 min. Thereafter the mixture is cooled in an ice bath and renderedneutral with acetic acid The mixture is extracted with ether. Theextract is dried (Na₂ SO₄) and concentrated. Chromatography of theresidue on silica gel using ethyl acetate-benzene (1:4) as eluant givesthe title compound, nmr (CDCl₃) δ 0.88 (3xm, 9H), 3,68 - 3.8 (3xm, 9H),5.5 (2xm, 4H).

EXAMPLE 45 Diethyl cis,trans-3-(6-carboethoxy-2-hexenyl)-4-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate(6, m = 2, n = 3, Z = -CH=CHCH₂ --, R¹, R⁵ and R⁸ = C₂ H₅, R² = CH₃, R³,R⁴ and R⁷ = H)

To a mixture of the compound of formula 4, diethyltrans-2-{3-[(tetrahydropyran-2-yl)oxy]-3-methyl-1-octenyl}cyclopropane-1,1-dicarboxylate(20.4 g), described in Example 41, and the compound of formula 5,triethyl cis-3-heptene-1,1,7-tricarboxylate (15.08 g), described inExample 42, a solution of 1.27 g of sodium in 50 ml of methanol is addedat room temperature. The methanol is removed under slightly reducedpressure. The residue is heated at 135°- 140°C for 1 hr. while keeping aslightly reduced pressure in the reaction flask. Saturated NaCl solutionis added and the mixture rendered neutral with acetic acid. The mixtureis extracted with ether. The extract is dried (Na₂ SO₄) andconcentrated. Chromatography of the residue on silica gel [eluant =ethyl acetate-benzene (1:4)] yields diethyl cis,trans-3-(6-carboethoxy-2-hexenyl)-4-{3-[(tetrahydropyran-2-yl)oxy]-3-methyl-1-octenyl}-2-oxo-1,3-cyclopentanedicarboxylate, γ_(max) .sup. EtOH 291 nm ε =13,400) in the presence of base (NaOH).

A solution of the latter compound (10.5 g) in 80 ml of methanol-water(9:1) and 1.0 g of p-toluenesulfonic acid monohydrate is left at roomtemperature for 15 min. and then rendered neutral with aqueous NaHCO₃.The methanol is evaporated and after addition of saturated NaCl, themixture is extracted with ether. The ether layer is dried (Na₂ SO₄).Evaporation of the solvent gives a residue, which on purification bychromatography on silica gel affords the title compound, nmr (CDCl₃)δ0.84 (t, J = 6, 3H), 1.22 (2xm, 6H), 4.16 (m 6H), 5.35 (m, 2H), 5.56(m, 2H).

By following the procedures of Examples 44 and 45 and using theappropriate compounds of formulae 4 and 5 as starting materials, othercyclopentanonetriesters of formula 6 are obtained.

For example, the use of the compound of formula 4, diethyltrans-2-{3-[(tetrahydropyran-2-yl)oxy]-3-methyl-1-octenyl}cycloprane-1,1-dicarboxylate,described in Example 41, and the compound of formula 5, triethylheptane-1,1,7-tricarboxylate, described in Example 42, in the procedureof Example 45 gives diethyltrans-3-(6-carboethoxyhexanyl)-4-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate,γ_(max) ^(film) 3500, 1725 cm⁻ ¹, nmr (CDCl₃) δ 0.88 (t, 3H), 4.17 (m,6H), 5.64 (m, 2H), via the intermediate diethyltrans-3-(6-carboethoxyhexanyl)-4-{3-[(tetrahydropyran-2-yl)oxy]-3-methyl-1-octenyl}-2-oxo-1,3-cyclopentanedicarboxylate,γ_(max) ^(film) 1730 cm⁻ ¹.

Likewise, the use of diethyltrans-2-{3-[(tetrahydropyran-2-yl)oxy]-4-methyl-1-octenyl}cyclopropane-1,1-dicarboxylateand triethyl cis-3-heptene-1,1,7-tricarboxylate gives diethyl cis,trans-3-(6-carboethoxy-2-hexenyl)-4-(3-hydroxy-4-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate,γ_(max) ^(film) 3500 cm⁻ ¹, γ_(max) ^(EtOH) 291 nm (ε = 13,600) in thepresence of base (NaOH).

Likewise, the utilization of diethyltrans-2-{3-[(tetrahydropyran-2-yl)oxy]-3-methyl-1-octenyl}cyclopropane-1,1-dicarboxylate, and triethyl cis-4-heptene-1,1,7-tricarboxylate,described in Example 43, gives diethyl cis,trans-3-(6-carboethoxy-3-hexenyl)-4-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate,nmr (CDCl₃) δ 0.89 (t, J = 5, 3H), 1.13 to 1.4 (m, 6H), 2.33 (2H), 4.2(m, 2H), 5.4 (m, 2H), 5.65 (m, 2H).

Additional examples of compounds of formula 6 are listed in Table IIItogether with the requisite starting materials. It is to be noted thatwhen the procedure of Example 45 is used the requisite starting materialof formula 4 is the corresponding tetrahydropyran-2-yl ether derivativeof the compound of formula 4 noted therein; the tetrahydropyran-2-ylether being prepared by following the procedure described in Example 41.Preparation of the starting materials of formula 5, i.e. triesters offormula 5, is described in Examples 42 and 43.

                                      TABLE III                                   __________________________________________________________________________    NO. OF EXAMPLE                                                                IN WHICH STARTING                                                             MATERIAL OF     STARTING MATERIAL OF                                                                        PRODUCT: (PREFIX LISTED                         FORMULA 4       FORMULA 5     BELOW)-2-oxo-1,3-CYCLO-                         EX: IS DESCRIBED                                                                               Z     m R .sup.1 and R.sup.8                                                               PENTANEDICARBOXYLATE                            __________________________________________________________________________    46     18       (CH.sub.2).sub.3                                                                     2 CH.sub.3                                                                           dimethyl trans-3-(6-carbo-                                                    methoxyhexyl)-4-(4-ethyl-                                                     3-hydroxy-1-heptenyl)                           47     19       CH= CHCH.sub.2                                                                       1 C.sub.2 H.sub.5                                                                    diethyl cis, trans-3-(5-car-                                                  boethoxy-2-pentenyl)-4-(3-                                                    hydroxy-4-propyl-1-nonenyl)                     48     20       CH.sub.2 CH=CH                                                                       0 CH.sub.3                                                                           dimethyl cis, trans-3-(4-                                                     carbomethoxy-3-butenyl)-4-                                                    (4-ethyl-3-hydroxy-1-decen-                                                   yl)                                             49     21       (CH.sub.2).sub.3                                                                     1 C.sub.2 H.sub.5                                                                    diethyl trans-3-(5-carbo-                                                     ethoxypentyl)-4-(3-hydroxy-                                                   4-methyl-1-heptenyl)                            50     22       CH=CHCH.sub.2                                                                        2 CH.sub.3                                                                           dimethyl cis, trans-3-(6-                                                     carbomethoxy-2-hexenyl)-4-                                                    (3-hydroxy-4-methyl-1-                                                        nonenyl)                                        51     23       CH.sub.2 CH=CH                                                                       1 C.sub.2 H.sub.5                                                                    diethyl cis, trans-3-(5-                                                      carboethoxy-3-pentenyl)-4-                                                    (4-ethyl-3-hydroxy-1-                                                         octenyl)                                        52     24       (CH.sub.2).sub.3                                                                     0 CH.sub.3                                                                           dimethyl trans-3-(4-carbo-                                                    methoxybutyl)-4-(4-ethyl-                                                     3-hydroxy-1-decenyl)                            53     25       CH=CHCH.sub.2                                                                        1 C.sub.2 H.sub.5                                                                    diethyl cis, trans-3-(5-                                                      carboethoxy-2-pentenyl)-4-                                                    (3-hydroxy-4-propyl-1-                                                        heptenyl)                                       54     26       CH.sub.2 CH=CH                                                                       2 CH.sub.3                                                                           dimethyl cis, trans-3-(6-                                                     carbomethoxy-3-hexenyl)-4-                                                    (3-hydroxy-4-propyl-1-                                                        nonenyl)                                        55     27       (CH.sub.2).sub.3                                                                     1 n-C.sub.3 H.sub.7                                                                  dipropyl trans-3-(5-carbo-                                                    propoxypentyl)-4-(3-                                                          hydroxy-4,4-dimethyl-1-                                                       decenyl)                                        56     28       CH=CHCH.sub.2                                                                        0 n-C.sub.3 H.sub.7                                                                  dipropyl cis, trans-3-(4-                                                     carbopropoxy-2-butenyl)-4-                                                    (4-ethyl-(3-hydroxy-4-                                                        methyl-1-decenyl)                               57     29       CH.sub.2 CH=CH                                                                       1 CH.sub.3                                                                           dimethyl cis, trans-3-(5-                                                     carbomethoxy-3-pentenyl)-                                                     4-(3-hydroxy-(4-methyl-4-                                                     propyl-1-heptenyl)                              58     30       (CH.sub.2).sub.3                                                                     2 C.sub.2 H.sub.5                                                                    diethyl trans-3-(6-carbo-                                                     ethoxyhexyl)-4-(3-hydroxy-                                                    4,4-dipropyl-1-nonenyl)                         59     32       (CH.sub.2).sub.3                                                                     2 CH.sub.3                                                                           dimethyl trans-3-(6-                                                          carbomethoxyhexyl)-4-                                                         (3-hydroxy-3-methyl-1-                                                        heptenyl)                                       60     33       CH=CHCH.sub.2                                                                        1 C.sub.2 H.sub.5                                                                    diethyl cis, trans-3-                                                         (5-carboethoxy-2-                                                             pentenyl)-4-(3-ethyl-                                                         3-hydroxy-1-nonenyl)                            61     34       CH.sub.2 CH=CH                                                                       0 CH.sub.3                                                                           dimethyl cis, trans-3-                                                        (4-carbomethoxy-3-butenyl)-                                                   4-(3-hydroxy-3-propyl-1-                                                      decenyl)                                        62     35       (CH.sub.2).sub.3                                                                     1 C.sub.2 H.sub.5                                                                    diethyl trans-3-(5-                                                           carboethoxypentyl)-4-                                                         (3-hydroxy-3,4-dimethyl-                                                      1-heptenyl)                                     63     36       CH=CHCH.sub.2                                                                        2 CH.sub.3                                                                           dimethyl cis, trans-3-                                                        (6-carbomethoxy-2-                                                            hexenyl)-4-(3-ethyl-3-                                                        hydroxy-4-methyl-1-                                                           nonenyl)                                        64     37       CH.sub.2 CH=CH                                                                       1 C.sub.2 H.sub.5                                                                    diethyl cis, trans-3-                                                         (5-carboethoxy-3-                                                             pentenyl)-4-(4-ethyl-3-                                                       hydroxy-3-propyl-1-                                                           octenyl)                                        65     38       (CH.sub.2).sub.3                                                                     0 CH.sub.3                                                                           dimethyl trans-3-(4-                                                          carbomethoxybutyl)-4-                                                         (4-ethyl-3-hydroxy-3-                                                         methyl-1-decenyl)                               66     39       CH=CHCH.sub.2                                                                        1 C.sub.2 H.sub.5                                                                    diethyl cis, trans-3-                                                         (5-carboethoxy-2-                                                             pentenyl)-4-(3-ethyl-                                                         3-hydroxy-4-propyl-1-                                                         heptenyl)                                       67     40       CH.sub.2 CH=CH                                                                       2 CH.sub.3                                                                           dimethyl cis, trans-3-                                                        (6-carbomethoxy-3-                                                            hexenyl)-4-(3-hydroxy-                                                        3,4-dipropyl-1-nonenyl)                         __________________________________________________________________________

EXAMPLE 68 trans,cis-7-[2-(3-Hydroxy-3-methyl-1-octenyl)-5-oxo-cyclopentyl]-5-heptenoicAcid (1, m = 2, n = 3, X and Y = O, Z = CH=CHCH₂, R¹, R³ and R⁴ = H andR² = CH₃)

The cyclopentanonetriester of formula 6, diethylcis,-trans-3-(6-carboethoxy-2-hexenyl)-4-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate(11.2 g), described in Example 45, is heated to reflux for 1 hr. in asolution of sodium hydroxide (13.4 g) in 80 ml of water and 110 ml ofmethanol. The mixture is cooled, adjusted to pH 5 with 2N HCl, dilutedwith saturated sodium chloride solution and extracted with ether. Theether extract is dried (Na₂ SO₄) and concentrated. Chromatography onsilica gel yields the title compound ν_(max) ^(CHCl) 3 3580, 1740, 1720cm⁻ ¹, nmr (CDCl₃) δ 0.88 (t, J = 5, 3H), 1.28 (s, 3H), 5.3 - 5.75 (m,4H), 6.3 (2xs, 2H).

By following the procedure of Example 68 and using the appropriatecyclopentanonetriester of formula 6, for example those described inExamples 45 to 67, then other compounds of formula 1 in which X and Ytogether represent oxo and R¹ is hydrogen are obtained.

For example, the use of the cyclopentanonetriester of formula 6, diethyltrans-3-(6-carboethoxyhexanyl)-4-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate,described in Example 45, in the procedure of Example 68, givestrans-7-[2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentyl]-heptanoicacid, nmr (CDCl₃) δ0.88 (t, 3H), 5.52 (m, 2H), 6.6 (broad singlet, 2H).

Likewise, the use of diethyl cis,trans-3-(6-carboethoxy-2-hexenyl)-4-(3-hydroxy-4-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate,described in Example 45, gives trans,cis-7-[2-(3-hydroxy-4-methyl-1-octenyl)-5-oxocyclopentyl]-5-heptenoicacid, γ_(max) ^(film) 3450, 1725, 1710 cm⁻ ¹.

Likewise, the use of diethyl cis,trans-3-(6-carboethoxy-3-hexenyl)-4-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate,described in Example 45, gives trans,cis-7-[2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentyl]-4-heptenoicacid, γ_(max) ^(film) 3620, 3000, 1740, 1720 cm⁻ ¹, nmr (CDCl₃) δ 0.89(t, J = 5, 3H), 2.4 (4H), 5.4 (m, 2H), 5.65 (m, 2H), 5.9 (broad singlet,2H).

Likewise, the use of dimethyl cis,trans-3-(6-carbomethoxy-2-hexenyl)-4-(3-hydroxy-4,4-dimethyl-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate,described in Example 44, gives trans,cis-7-[2-(3-hydroxy-4,4-dimethyl-1-octenyl)-5-oxocyclopentyl]-5-heptenoicacid, γ_(max) ^(film) 3400 - 3000, 1730, 1710 cm⁻ ¹, nmr (CDCl₃) δ 0.85(m, 9H), 3.9 (m, 1H), 5.42 (m, 2H), 5,68 (m, 2H), 6.75 (broad s, 2H).

Further examples of such compounds of formula 1 are listed in Table IVtogether with the requisite cyclopentanonetriesters starting material,the latter compound being noted by the example describing itspreparation.

                                      TABLE IV                                    __________________________________________________________________________          NO. OF EXAMPLE IN WHICH                                                       CYCLOPENTANONETRIESTER                                                  EXAMPLE                                                                             OF FORMULA 4 IS PREPARED                                                                     PRODUCT:                                                 __________________________________________________________________________    69         46        trans-7-[2-(4-ethyl-3-hydroxy-                                                1-heptenyl)-5-oxocyclopentyl]-                                                heptanoic acid                                           70         47        trans, cis-6-[2-(3-hydroxy-                                                   4-propyl-1-nonenyl)-5-oxocyclo-                                               pentyl]-4-hexenoic acid                                  71         48        trans, cis-5-[2-(4-ethyl-3-                                                   hydroxy-1-decenyl)-5-oxocyclo-                                                pentyl]-2-pentenoic acid                                 72         49        trans-6-[2-(3-hydroxy-4-methyl-                                               1-heptenyl)-5-oxocyclopentyl]-                                                hexanoic acid                                            73         50        trans, cis-7-[2-(3-hydroxy-4-                                                 mwethyl-1-nonenyl)-5-oxocyclo-                                                pentyl]-5-heptenoic acid                                 74         51        trans, cis-6-[2-(4-ethyl-3-                                                   hydroxy-1-octenyl)-5-oxocyclo-                                                pentyl]-3-hexenoic acid                                  75         52        trans-5-[2-(4-ethyl-3-hydroxy-                                                1-decenyl)-5-oxocyclopentyl]-                                                 pentanoic acid                                           76         53        trans, cis-6-[2-(3-hydroxy-4-                                                 propyl-1-heptenyl)-5-oxocyclo-                                                pentyl]-4-hexenoic acid                                  77         54        trans, cis-7-[2-(3-hydroxy-4-                                                 propyl-1-nonenyl)-5-oxocyclo-                                                 pentyl]-4-heptenoic acid                                 78         55        trans-6-[2-(4,4-dimethyl-3-                                                   hydroxy-1-decenyl)-5-oxocyclo-                                                pentyl]hexanoic acid                                     79         56        trans, cis-5-[2-(4-ethyl-4-                                                   methyl-3-hydroxy-1-decenyl)-5-                                                oxocyclopentyl]-3-pentenoic acid                         80         57        trans, cis-6-[2-(4-methyl-3-                                                  hydroxy-4-propyl-1-heptenyl)-5-                                               oxocyclopentyl]-3-hexenoic acid                          81         58        trans-7-[2-(3-hydroxy-4,4-dipropyl-                                           1-nonenyl)-5-oxocyclopentyl]-                                                 heptanoic acid                                           82         59        trans-7-[2-(3-hydroxy-3-methyl-                                               1-heptenyl)-5-oxocyclopentyl]--   heptanoic acid         83         60        trans, cis-6-[2-(3-ethyl-3-hydroxy-                                           1-nonenyl)-5-oxocyclopentyl]-                                                 4-hexenoic acid                                          84         61        trans, cis-5-[2-(3-hydroxy-3-                                                 propyl-1-decanyl)-5-oxocyclopent-                                             yl] -2-pentenoic acid                                    85         62        trans-6-[2-(3-hydroxy-3,4-dimethyl-                                           1-heptenyl)-5-oxocyclopentyl]-                                                hexanoic acid                                            86         63        trans, cis-7-[2-(3-ethyl-3-hydroxy-                                           4-methyl-1-nonenyl)-5-oxocyclo-                                               pentyl]-5-heptenoic acid                                 87         64        trans, cis-6-[2-(4-ethyl-3-hydroxy-                                           3-propyl-1-octenyl)-5-oxocyclo-                                               pentyl]-3-hexenoic acid                                  88         65        trans-5-[2-(4-ethyl-3-hydroxy-                                                3-methyl-1-decenyl)-5-oxocyclo-                                               pentyl]pentanoic acid                                    89         66        trans,cis-6-[2- (3-ethyl-3-hydroxy-                                           4-propyl-1-heptenyl)-5-oxocyclo-                                              pentyl]-4-hexenoic acid                                  90         67        trans, cis-7-[2-(3-hydroxy-3,4-                                               dipropyl-1-nonenyl)-5-oxocyclo-                                               pentyl]-4-heptenoic acid                                 __________________________________________________________________________

EXAMPLE 91 Methyl trans,cis-7-[2-(3-hydroxy-4,4-dimethyl-1-octenyl)-5-oxocyclopentyl]-5-heptenoate(1; m =2, n = 3, X and Y = O, Z = CH=CHCH₂, R¹, R³ and R⁴ = CH₃ and R² =H)

The compound of formula 1, trans,cis-7 -[2-(3-hydroxy-4,4-dimethyl-1-octenyl)-5-oxocyclopentyl]-5-heptenoic acid (11.1 g),described in Example 68, is dissolved in 44 ml of absolute methanolcontaining 2% perchloric acid. The solution is kept at room temperaturefor 30 min. Thereafter the mixture is rendered neutral with 10% Na₂ CO₃and concentrated. The residue is diluted with water and shaken withether. The ether layer is washed with water, dried (MgSO₄) andconcentrated to yield the title compound, γ_(max) ^(film) 3600 - 3400,1730, 1710 cm⁻ ¹.

The latter compound is a mixture of the epimers with respect to theasymmetric carbon to which the hydroxy group is attached, each epimerbeing a racemate consisting of a d l pair of stereochemical isomers. Bysubjecting the preceding product to chromatography on silica gel usingethyl acetate-benzene (1:4) as eluant, the product is separated into itstwo epimeric forms which are arbitrarily designated isomer A (leastpolar isomer) and Isomer B (most polar isomer); the polarity beingdetermined by the order in which these epimers are eluted.

Isomer A: γ_(max) ^(film) 3470, 1730 cm⁻ ¹, nmr (CDCl₃) δ 0.85 (9H),3.68 (s, 3H), 3.82 (m, 1H), 5.4 - 5.7 (m, 4H), Rf = 0.88 on thin layerplates of silica gel when using ethyl acetate-benzene (2:3) as themobile phase.

Isomer B: γ_(max) ^(film) 3470, 1730 cm⁻ ¹, nmr (CDCl₃) δ 3.67 (s, 3H),3.82 (m, 1H), 5.41 (m, 2H), 5.66 (m, 2H), Rf = 0.69 on thin layer platesof silica gel when using ethyl acetate-benzene (2:3) as the mobilephase.

In the same manner but using the appropriate choice of the compound offormula 1 and lower alkanol, other corresponding esters of formula 1 (R¹= lower alkyl) are prepared; for example, the corresponding lower alkylesters of the products of Table IV. More specifically exemplified, thechoice oftrans-7-[2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentyl]heptanoicacid, described in Example 68, as the compound of formula 1 and methanolas the lower alkanol in the procedure of this example give methyltrans-7-[2-(3-hydroxy-3-methyl-1-octenyl)5-oxocyclopentyl]heptanoate,γ_(max) ^(film) 3475, 1730 cm⁻ ¹, nmr (CDCl₃) δ 0.89 (t, 3H), 3.64 (s,3H), 5.61 (m, 2H).

Likewise, the choice of trans,cis-7-[2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentyl]-5-heptenoicacid described in Example 68, and methanol, gives methyl trans,cis-7-[2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentyl]-5-heptenoate,γ_(max) ^(film) 1738, 1730 cm⁻ ¹.

Likewise, the choice of trans,cis-7-[2-(3-hydroxy-4-methyl-1-octenyl)-5-oxocyclopentyl]-5-heptenoicacid and methanol gives methyl trans,cis-7-[2-(3-hydroxy-4-methyl-1-octenyl)-5-oxocyclopentyl]-5-heptenoate,γ_(max) ^(film) 1732 cm⁻ ¹, nmr (CDCl₃) δ 3.65 (s, 3H), 5.25 - 5.75 (m,4H).

Likewise, the choice of trans,cis-7-[2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentyl]-4-heptenoicacid and ethanol gives ethyl trans,cis-7-[2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentyl]-4-heptenoate,δ_(max) ^(film) 1740, 1732 cm⁻ ¹.

EXAMPLE 92 Methyl trans,cis-7-[2-hydroxy-5-(3-hydroxy-4,4-dimethyl-1-octenyl)cyclopentyl]-5-heptenoate(1; m = 2, n = 3, X = OH, Y = H, Z = CH=CHCH₂, R¹, R³ and R⁴ = CH₃ andR² = H)

A solution of borane (11 ml of 1M soln.) in THF is added to a solutionof pinene (2.99 g) in dry diglyme (8.0 ml) at -10°C (bath temp.) in a N₂atmosphere. The mixture is stirred for 10 min. then cooled to -78°C. Tothis mixture tert-butyl lithium (5.5 ml, 2.1 molar in pentane) is addedslowly, maintaining the temp. of the reaction at -78°C. After stirringfor 10 min., a solution of methyl trans,cis-7-[2-(3-hydroxy-4,4-dimethyl-1-octenyl)-5-oxocyclopentyl]-5-heptenoate,Isomer B (1.37 g), described in Example 91, in diglyme-THF (8.8 ml,1:0.7) is added to the mixture. The temperature is maintained at -78°Cfor one hour. The cooling bath is removed and, the reaction is quenchedby adding 10% sodium hydroxide solution (8ml) and 30% hydrogen peroxidesolution (8 ml). The mixture is then diluted with water and extractedwith ether. The ether extract is washed with water and 3% HCl soln. torender it neutral, dried (MgSO₄) and concentrated to yield the titlecompound (Isomer B) γ_(max) ^(film) 3600 - 3440, 1730 - 1720 cm⁻ ¹. Thisproduct is a mixture of epimers with the respect to the asymmetriccarbon of the cyclopentane ring to which the hydroxy group is attached,each epimer being a racemate consisting of a d l pair of stereochemicalisomers. The product is separated into these two epimers by subjectingit to chromatography on silica gel (135 g) using ethyl acetate-benzene(1:4) as eluant. In this manner the product is separated into a firstepimer (less polar) and a second eqimer (more polar):

Less polar epimer γ_(max) ^(film) 3400, 1730 - 1720 cm⁻ ¹, nmr (CDCl₃) δ0.88 (m, 9H), 3.68 (s, 3H), 3.79 (m, 1H), 4.2m, 1H), 5.5 (m, 4H), Rf =0.52 on thin layer plates of silica gel when using ethyl acetate-benzene(2:3) as the mobile phase.

More polar epimer γ_(max) ^(film) 3400, 1726 cm⁻ ¹, nmr (CDCl₃) δ 0.88(m, 9H), 3.67 - 3.95 (m, 5H), 5.52 (m, 4H), Rf = 0.41 on thin layerplates of silica gel when using ethyl acetate-benzene (2:3) as themobile phase.

Comparative data with the nmr spectra of known hydroxyprostaglandinderivatives, for example see J. F. Bagli and T. Bogri, tetrahedronLetters, 1639 (1969), and the order of elution of knownhydroxyprostaglandin derivates, see for example J. E. Pike, et al., J.Org. Chem., 34, 3552 (1969), indicate that the C-2 hydroxy group and theC-l acid side chain of the above less polar epimer have a cisrelationship whereas the C-2-hydroxy group and the C-1 acid side chainof the above more polar epimer have a trans relationship.

In other words the data indicate that the less polar epimer is racemicmethyl trans,cis-7-[2α-hydroxy-5-(3-hydroxy-4,4-dimethyl-1-octenyl)cyclopentyl]-5-heptenoateand the more polar isomer is racemic methyl trans,cis-7-[2β-hydroxy-5-(3-hydroxy-4,4-dimethyl-1-octenyl)cyclopentyl]-5-heptenoate.

In the same manner but replacing methyl trans,cis-7-[2-(3-hydroxy-4,4-dimethyl-1-octenyl)-5-oxocyclopentyl]-5-heptenoate,Isomer B, with the corresponding Isomer A, described in Example 91,Isomer A of the title compound is obtained, γ_(max) ^(film) 3600, 1732 -1720 cm⁻ ¹, which in turn can be separated into its less polar and morepolar epimer. The less polar epimer of Isomer A, racemic methyl trans,cis-7-[2α-hydroxy-5-(3-hydroxy-4,4-dimethyl-l-octenyl)cyclopentyl]-5-heptenoate[nmr (CDCl₃) δ 4.2] has a Rf = 0.68 on thin layer plates of silica gelusing ethyl acetate-benzene (2:3) as the mobile phase and the more polarepimer of Isomer A, racemic methyl trans,cis-7-[2β-hydroxy-5-(3-hydroxy-4,4-dimethyl-l-octenyl)cyclopentyl]-5-heptanoate[nmr (CDCl₃) δ 3.7 - 3.9] has a Rf = 0.47 on silica gel plates usingethyl acetate-benzene (2:3) as the mobile phase.

In the same manner but using the appropriate oxo compound of formula l,other corresponding hydroxy compounds of formula l in which X ishydroxy, Y is hydrogen and R¹ is lower alkyl are prepared; for example,the corresponding lower alkyl esters of the hydroxy compounds of theproducts of Table IV.

More specifically exemplified the choice of the oxo compound of formulal, methyltrans-7-[2-(3-hydroxy-3-methyl-l-octenyl)-5-oxocyclopentyl]heptanoate,described in Example 91, in the procedure of this example gives methyltrans-7-[2-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]-heptanoate,γ_(max) ^(film) 3410, 1730 cm⁻ ¹.

Likewise, the choice of methyl trans,cis-7-[2-(3-hydroxy-3-methyl-l-octenyl)-5-oxocyclopentyl]-5-heptenoate,gives methyl trans,cis-7-[2-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl(cyclopentyl]-5-heptenoate,γ_(max) ^(film) 3600, 1735 cm⁻ ¹, which can be separated into it lesspolar and more polar epimer. The less polar epimer, racemic methyltrans,cis-7-[2α-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]-5-heptenoate[nmr (CDCl₃) δ 4.28] has a Rf = 0.36 on silica gel thin layer platesusing ethyl acetate-benzene (3:7) as the mobile phase and the more polarepimer racemic methyltrans,-cis-7-[2β-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]-5-heptenoate[nmr (CDCl₃) δ 3.90] has a Rf = 0.28 on silica gel thin layer platesusing the same mobile phase.

Likewise, the choice of methyltrans,cis-7-[2-(3-hydroxy-4-methyl-l-octenyl)-5-oxocyclopentyl]-5-heptenoate,described in Example 91, gives methyl trans,cis-7-[2-hydroxy-5-(3-hydroxy-4-methyl-l-octenyl)cyclopentyl]-5-heptenoate,γ_(max) ^(film) 3600, 1732 cm⁻ ¹.

Likewise, the choice of methyl trans,cis-7-[2-(3-hydroxy-3-methyl-l-octenyl)-5-oxocyclopentyl]-4-heptenoate,described in Example 91, gives methyl trans,cis-7-[2-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]-4-heptenoate,γ_(max) ^(film) 3600, 1730 cm⁻ ¹, which can be separated into its lesspolar and more polar epimer. The less polar epimer, racemic methyltrans,cis-7-[2α-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]-4-heptenoatehas nmr (CDCl₃) δ 2.38 (4H), 4.28 (1H), 5.5 (4H) and the more polarepimer racemic methyl trans,cis-7-[2δ-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]-4-heptenoatehas nmr (CDCl₃) δ 2.4 (4H), 3.98 (1H), 5.57 (4H).

EXAMPLE 93 trans,cis-7-[2-Hydroxy-5-(3-hydroxy-4,4-dimethyl-l-octenyl)-cyclopentyl]-5-heptenoicAcid (1), 1; m = 2, n = 3, X = OH, Y = H, Z = CH=CHCH₂, R¹ and R² = Hand R³ and R⁴ = CH₃)

To a solution of trans,cis-7-[2-hydroxy-5-(3-hydroxy-4,4-dimethyl-l-octenyl)cyclopentyl]-5-heptenoate(0.536 g, Isomer B less polar epimer), described in Example 92, inmethanol (5 ml) is added a solution of sodium hydroxide (10%, 1.32 ml).The mixture is stirred for 18 hr. The solvent is removed under reducedpressure and the residue taken up in water and extracted with ether. Theaqueous liquor is then rendered acidic with HCl (10%, 1.32 ml). Theprecipitate is taken up with ether. The ether extract is washed withwater, dried (Na₂ SO₄) and the solvent is removed to yield the titlecompound, Isomer B less polar epimer, nmr (CDCl₃) δ 0.84 (m, 9H), 3.80(m, 1H), 4.23 (m, 1H), 5.27 (broad, 3H), 5.5 (m, 4H), (i.e., racemictrans, cis-7-[2α-hydroxy-4,4-dimethyl-l-octenyl)cyclopentyl]-5-heptenoicacid).

In the same manner the Isomer B-more polar epimer, Isomer A-more polarepimer and the Isomer A-less polar epimer of methyl trans,cis-7-[2-hydroxy-5-(3-hydroxy-4,4-dimethyl-l-octenyl)cyclopentyl]-5-heptanoate,described in Example 92, are converted to the respective Isomer B-morepolar epimer, Isomer A-more polar epimer and the Isomer A-less polarIsomer of the title compound.

In the same manner but using the appropriate ester compound of formula lin which X is hydroxy, Y is hydrogen and R¹ is hydrogen are prepared;for example the corresponding hydroxy compounds of the products of TableIV.

More specifically exemplified, the choice of methyltrans-7-[2-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]-heptanoate,described in Example 92, in the procedure of this example givestrans-7-[2-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)-cyclopentyl]heptanoicacid, nmr (CDCl₃) δ 0.9 (t, 3H), 4.0 - 4.3 (m, 1H), 5.5 (m, 2H).

Likewise, the choice of methyltrans-7-[2-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]heptanoate,more polar or less polar epimer, described in Example 94, gives therespective more polar [nmr (CDCl₃) δ 3.95] and less polar epimer [nmr(CDCl₃) δ 4.25] oftrans-7-[2-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)-cyclopentyl]heptanoicacid. In other words trans-7-[2β-hydroxy-andtrans-7-[2α-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]-heptanoicacid are obtained, respectively (see Example 92 for the significance ofthe nmr peaks).

Likewise, the choice of methyl trans,cis-7-[2-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]-5-heptenoate,described in Example 92, gives trans,cis-7-[2-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]-5-heptenoicacid, γ_(max) ^(film) 3610, 3450, 1718 cm⁻ ¹.

Likewise, the choice of methyl trans,cis-7-[2-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]-5-heptenoate,more polar and less polar epimer, described in Example 92, gives therespective more polar [nmr (CDCl₃) δ 3.95 (1H), 5.55 (2H)] and lesspolar epimer [nmr (CDCl₃) δ 4.27 (1H), 5.5 (2H)], namely trans,cis-7-[2β-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)-cyclopentyl]-5-heptenoicacid and trans,cis-7-[2α-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]-5-heptenoicacid respectively.

Likewise, the choice of methyl trans,cis-7-[2-hydroxy-5-(3-hydroxy-4-methyl-l-octenyl)cyclopentyl]-5-heptenoate,described in Example 92, gives trans,cis-7-[2-hydroxy-5-(3-hydroxy-4-methyl-l-octenyl)cyclopentyl]-5-heptenoicacid.

Likewise, the choice of the less and more polar epimer of methyl trans,cis-7-[2-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)-cyclopentyl]-4-heptenoate,described in Example 92, gives the respective less and more polar epimerof trans,cis-7-[2-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]-4-heptenoicacid. In other words, trans,cis-7-[2α-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)-cyclopentyl]-4-heptenoicacid [nmr (CDCl₃) δ 4.28] and trans,cis-7-[2β-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]-4-heptenoicacid [nmr (CDCl₃) δ 3.98] are obtained, respectively.

EXAMPLE 94 Methyltrans-7-[2-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)-cyclopentyl]heptanoate(1;, m = 2, n = 3, X = OH, Y = H, Z = (CH₂)₃, R¹ and R² = CH₃, R³ and R⁴= H)

The compound of formula 3, methyltrans-7-[2-(3-oxo-l-octenyl)-5-(trimethylsilyloxy)cyclopentyl]heptanoate[3; R³ and R⁴ = H, n = 3 and L = radical B wherein Z = (CH₂)₃, m = 2, R¹= CH₃ and R⁶ = Si(CH₃)₃ ], γ_(max) ^(film) 1737, 1678, 1625 cm⁻ ¹, nmr(CDCl₃) δ 0.12 (9H), 0.9 (3H), 3.68 (3H), 4.24 (1H), 6.5 (2H), isprepared by treating the precusor to the aldehyde of formula L--CHO inwhich L is the radical B, 2-(6-carboxyhexyl)cyclopentan-l-ol-3-al,prepared as described in copending application Ser. No. 259,896, notedabove, with 1.2 equivalents of both trimethylchlorosilane andhexamethyldisilazane in THF at 60° C for one hour, followed by treatmentof the resulting aldehyde of formula L--CHO with dimethyl2-oxoheptylphosphonate according to the procedure of Example 2.Alternatively, the last named compound of formula 3 is prepared bytreating methyltrans-7-[2-(3-oxo-l-octenyl)-5-hydroxycyclopentyl]heptanoate, describedin U.S. Pat. No. 3,455,992, issued July 15, 1969, withtrimethylchlorosilane and hexamethyldisilazane in the same manner.

The said last named compound of formula 3 (18.76 g) in dry ether (80 ml)is cooled to -5° C and added to a solution of methyl magnesium iodide(prepared from 1.23 g of magnesium turnings and 7.63 g of methyl iodide)in 100 ml of dry ether at -5° C. After 15 min. of stirring the reactionmixture is quenched with 10 ml of saturated ammonium chloride (10 ml)while maintaining the temperature at -5 to 0° C. The mixture is dilutedwith ether, washed with water, dried (Na₂ SO₄) and concentrated to yieldmethyltrans-7-[2-(3-hydroxy-3-methyl-l-octenyl)-5-(trimethylsilyloxy)cyclopentyl]heptanoate[4; R² = CH₃, R³, R⁴ and R⁷ = H, n = 3 and L = radical B wherein Z =(CH₂)₃, m= 2, R¹ = CH₃ and R⁶ = Si(CH₃)₃ ], γ_(max) ^(film) 3400, 1740,1712, 1250, 848 cm⁻ ¹, nmr (CDCl₃) δ 0.1 (9H), 0.92 (3H, 1.3 (s, 3H),3.7 (s, 3H), 5.5 (m, 2H)

The latter compound (18.85 g) in THF (16.8 ml), water (47.2 ml) andacetic acid (25 ml) is stirred at room temperature for 2 hr. The mixtureis cooled in an ice bath and rendered neutral by the careful addition ofsodium carbonate (20 g). The mixture is extracted with ether. The etherextract is washed with water, dried (Na₂ SO₄) and concentrated to yieldthe title compound, γ_(max) ^(film) 3410, 1730 cm⁻ ¹, identical to theproduct of the same name described in Example 92. This product is amixture of epimers with respect to the asymmetric carbon of thecyclopentane ring to which the hydroxy group is attached. In the samemanner as for the title compound of Example 92, the present product isseparated into a first epimer (less polar) and second epimer (morepolar):

Less polar epimer: γ_(max) ^(film) 3430, 1730 cm⁻ ¹, nmr (CDCl₃) δ 0.90(t, 3H), 3.68 (s, 3H), 4.2 (m, 1H), 5.5 (m, 2H),

More polar epimer: γ_(max) ^(film) 3350, 1730 cm⁻ ¹, nmr (CDCl₃) δ 0.88(t, 3H), 3.68 (s, 3H), 3.90 (m, 1H), 5.55 (m, 2H).

As discussed in Example 92, comparative data with the spectra of knownhydroxyprostaglandin derivatives indicate that the preceding less polarepimer is a racemic mixture of methyltrans-7-[2α-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]heptanoateand that the preceding more polar isomer is racemic mixture of methyltrans-7-[2β-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]heptanoate.The respective Rf's of these two racemic mixtures are 0.44 and 0.29 onthin layer plates of silica gel when using ethyl acetate-benzene (1:4)as the mobile phase.

In the same manner but replacing methyl magnesium iodide with anequivalent amount of ethyl magnesium bromide or propyl magnesiumbromide, methyltrans-7-[2-(3-hydroxy-3-propyl-l-octenyl)-5-hydroxycyclopentyl]-5-heptenoateand methyltrans-7-[2-(3-hydroxy-3-propyl-l-octenyl)-5-hydroxycyclopentyl]-5-heptenoateare obtained, respectively.

In the same manner but replacing the compound of formula 3, methyltrans-7-[2-(3-oxo-l-octenyl)-5-(trimethylsilyloxy)-cyclopentyl]-5-heptenoate,with the appropriate compound of formula 3 in which L is radical B, thenother compound of formula 1 in which m, n, Z, R², R³ and R⁴ are asdefined in the first instance X is hydroxy, Y is hydrogen and R¹ islower alkyl are obtained; for example, the products of formula 1 inwhich R² is methyl described in Example 92. More specificallyexemplified, replacement of the compound of formula 3 with methyl trans,cis-7-[2-(3-oxo-l-octenyl)-5-[(tetrahydropyran-2-yl)oxy]cyclopentyl]-5-heptenoategives methyltrans,cis-7-[2-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]-5-heptenoate,described in Example 92.

EXAMPLE 95 Methyltrans-7-[2-(3-hydroxy-3-methyl-l-octenyl)-5-oxocyclopentyl]heptanoate(1; m = 2, n = 3, X and Y = 0, Z = (CH₂)₃, R¹ and R² = CH₃ and R³ and R⁴= H)

To a solution of dry pyridine (5.85 ml) in methylene chloride (135 ml,purified by shaking with H₂ SO₄, and dried over CaO, and distilled) isadded chromic acid (4 g) at 15° C. The mixture is stirred for 20 min. Tothis mixture is added a solution of the compound of formula 1 in whichR² is methyl, methyltrans-7-[2-hydroxy-5-(3-hydroxy-3-methyl-l-octenyl)cyclopentyl]heptanoate,described in Example 92, in methylene chloride (50 ml). The mixture isstirred for one hour. The reaction mixture is filtered and the collectedslurry on the filter pad is washed with more methylene chloride. Theorganic phase of the filtrate and washing are combined and washed withwater, dried (Na₂ SO₄) and the solvent concentrated, to yield the crudeproduct. Chromatography of the product on a silica gel column affordsthe title compound, identical to the product of the same name describedin Example 91.

In the same manner other compounds of formula 1 in which X is hydroxy, Yis hydrogen and R² is lower alkyl, for example the other compounds offormula 1 in which R² is methyl of Example 92, are oxidized to theircorresponding compounds of formula 1 in which R² is lower alkyl, forexample methyl.

EXAMPLE 96 Methyl trans,cis-7-[2-(3-hydroxy-4,4-dimethyl-l-octenyl]-5-oxocyclopentyl]-5-heptenoate(1; m = 2, n = 3, X and Y = 0, Z = (CH₂)₃, R¹ and R² = CH₃ and R³ and R⁴= H)

A mixture of the compound of formula 3 in which L is the radical C,methyltrans-7-[2-(4,4-dimethyl-3-oxo-l-octenyl)-5-oxocyclopentyl]-5-heptenoate(2.5 g, γ_(max) ^(film) 1730 - 1725, 1667, 1620 cm⁻ ¹), ethylene glycol(360 mg) and P-toluenesulfonic acid (35 mg) in 50 ml of benzene isheated at reflux for 2.5 hr. Thereafter the mixture is extracted withether. The ether extract is washed with water, dried (MgSO₄) andconcentrated under reduced pressure. The residue containing methyltrans,cis-7-[2-(ethylenedioxy)-5-(4,4-dimethyl-3-oxo-l-octenyl)cyclopentyl-5-heptenoate,γ_(max) ^(film) 1730, 1667, 1620 cm⁻ ¹, is taken up in 20 ml of methanoland treated with sodium borohydride (350 mg) in small portions withstirring which is continued for 30 minutes. The solvent is evaporatedunder reduced pressure, the residue taken up in ether, washed toneutrality with water, dried (MgSO₄) and the solvent concentrated underreduced pressure. The residue is chromatographed on silica gel (140 g).Elution with ethyl acetate-benzene (4:1) and concentration of the eluantaffords methyl trans,cis-7-[2-(ethylenedioxy)-5-(3-hydroxy-4,4-dimethyl-l-octenyl)cyclopentyl]-5-heptenoate,γ_(max) ^(film) 3460, 1740, 950 cm⁻ ¹.

The latter compound (50 mg) is dissolved in methanol water (9:1)containing 20 mg of p-toluenesulfonic acid. This mixture is allowed tostand at room temperature overnight. The mixture is diluted with etherand washed with water. The ether extract is dried (MgSO₄) and thesolvent evaporated under reduced pressure to yield the title compound,identical to the product of the same name described in Example 91.

In the same manner other compounds of formula 1 in which X and Ytogether are oxo, R¹ is lower alkyl and R² is hydrogen, for example, thecorresponding lower alkyl esters of Examples 69 to 81, are obtained byusing the appropriate corresponding compound of formula 3 in which L isthe radical C.

The requisite compounds of formula 3 in which L is the radical C areprepared by reacting the appropriate aldehyde of formula LCHO in which Lis the radical C, prepared by the procedure described in copending U.S.application Ser. No. 259,896, noted above, with the appropriate Wittigreagent of formula (AlkO)₂ POCH₂ COR³ R⁴ (CH₂)_(n) CH₃ in which at leastone of R³ and R⁴ is lower alkyl, described above, according to theprocedure of Example 2. For example, methyl trans,cis-7-[2-(4,4-dimethyl-3-oxo-l-octenyl)-5-oxocyclopentyl]-5-heptanoate,utilized above, is prepared by treating2-(6-carboxy-2-hexenyl)cyclopentane-l-on-3-al with the Wittig reagent,dimethyl 3,3-dimethyl-2-oxoheptyl phosphonate, described in Example 1,according to the procedure of Example 3.

EXAMPLE 97 Diethyltrans-2-(3-oxo-l-butenyl)cyclopropane-1,1-dicarboxylate (12; L = radicalA in which R⁵ = C₂ H₅ and R⁹ = CH₃)

A solution of diethyl 2-formylcyclopropane-1,1-dicarboxylate (14 g) inacetone (40 ml) is added slowly (about 5 hr. of addition time) to aboiling mixture of piperidine (3 ml) and acetone (140 ml). After thisaddition the reaction mixture is heated at reflux for an additionalhour. The excess acetone is removed under reduced pressure. The residueis diluted with water and extracted with benzene. The extract is dried(Na₂ SO₄) and evaporated to dryness. The residue is dissolved inacetonehexane (1:9) and the solution poured through a column of silicagel. The eluate is concentrated to give the title compound γ_(max)^(film) 1725, 1670, 1625 cm⁻ ¹, nmr (CDCl₃ δ 1.26 (t, J = 8, 3H), 1.8(m, 2H), 2.2 (3H), 2.6 (1H), 4.25 (q, 2H), 6.23 and 6.28 (2H).

In the same manner but replacing diethyl2-formylcyclopropane-1,1-dicarboxylate with dimethyl2-formylcyclopropane-1,1-dicarboxylate, the corresponding methyl esterof the title compound, dimethyltrans-2-(3-oxo-l-butenyl)cyclopropane-1,1-dicarboxylate is obtained.

Thereafter, by following the procedure of Example 31 but replacingdiethyl trans-2-(3-oxo-l-octenyl)cyclopropane-1,1-dicarboxylate andmethyl magnesium iodide with equivalent amounts of the title compoundand pentyl magnesium bromide, respectively, diethyltrans-2-(3-hydroxy-3-methyl-l-octenyl)cyclopropane-1,1-dicarboxylate,identical to the product of the same name described in Example 31, isobtained. Similarly the use of the title compound or its correspondingmethyl ester and the appropriate lower alkyl magnesium halide in whichthe alkyl portion is CR³ R⁴ --(CH₂)_(n) CH₃ in which R³ is hydrogen, R⁴is hydrogen or lower alkyl and n is as defined hereinbefore gives thecorresponding compound of formula 4; for example, the use of thecorresponding methyl ester of the title compound and butyl magnesiumiodide gives dimethyltrans-2-(3-hydroxy-3-methyl-l-heptenyl)cyclopropane-1,1-dicarboxylate,described in Example 32.

In the same manner but replacing acetone with an equivalent amount of2-butanone or 2-pentanone, diethyltrans-2-(3-oxo-l-pentenyl(cyclopropane-1,1-dicarboxylate and diethyltrans-2-(3-oxo-l-hexenyl(cyclopropane-1,1-dicarboxylate are obtained,respectively. Thereafter, and likewise, treatment of the appropriatechoice of one of the latter two compounds with the appropriate loweralkyl magnesium halide in which the alkyl portion is CR³ R⁴ --(CH₂)_(n)CH₃ in which R³, R⁴ and n are as defined in the last instance gives thecorresponding compound of formula 4.

EXAMPLE 98 Diethyltrans-2-(3-oxo-l-octenyl)cyclopropane-1,1-dicarboxylate (12; L = radicalA in which R⁵ = C₂ H₅ and R⁹ = n--C₅ H₁₁)

Equimolar quantities of the aldehyde of formula 2, diethyl2-formylcyclopropane-1,1-dicarboxylate, 2-heptanone and piperidine areheated at reflux in benzene (2.6 ml for each gram of aldehyde) for 2 - 5hr. The azeotrope is collected giving about one mole of water. Themixture is diluted with fresh benzene. The benzene layer is washed withwater, dried (Na₂ SO₄) and concentrated. The residue is subjected tochromatography [eluent = acetone - hexane (1:4)] to give the titlecompound identical to the product of the same name described in Example3.

In the same manner but replacing 2-heptanone with the appropriate methylketone of formula CH₃ COR⁹ in which R⁹ is CR³ R⁴ --(CH₂)_(n) CH₃ anddefined hereinbefore then other corresponding compounds of formula 12are obtained; for example, such replacement of 2-heptanone with3-methyl-2-heptanone or 2-nonanone gives diethyltrans-2-(4-methyl-3-oxo-l-octenyl)cyclopropane-1,1-dicarboxylate,described in Example 3, and diethyltrans-2-(3-oxo-l-decenyl)cyclopropane-1,1-dicarboxylate, respectively.##SPC9##

We claim:
 1. A process for preparing a compound of the formula 1, ##SPC10##in which m is an integer from zero to two, n is an integer from two to five, X and Y together represent oxo, or X represents hydroxy and Y is hydrogen, Z represents the radical --(CH₂)₃ -- cis-CH=CH--CH₂ -- or cis-CH₂ --CH=CH--, R¹ is hydrogen or lower alkyl and R², R³ and R⁴ each are hydrogen or lower alkyl with the provisos that at least one of R², R³ or R⁴ is lower alkyl and at least one of R², R³ or R⁴ is hydrogen, which comprises, treating an aldehyde of formula L--CHO (2) in which L is the radical A, ##SPC11## wherein R⁵ is lower alkyl, with a Wittig reagent of the formula (AlkO)₂ POCH₂ COCR³ R⁴ --(CH₂)_(n) CH₃ in which Alk is an alkyl containing one to three carbon atoms and R³, R⁴ and n are as defined herein, or with a methyl ketone of formula CH₃ COR⁹ in which R⁹ is CR³ R⁴ --(CH₂)_(n) -- CH₃ in which R³, R⁴ and n are as defined herein in the presence of a base, to obtain the corresponding compound of formula L--CH=CHCOCR³ R⁴ -- (CH₂)_(n) CH₃ (3), in which L, R³, R⁴ and n are as defined herein; treating the last-named compound of formula 3 with a metal borohydride or a lower alkyl magnesium halide to give the corresponding compound of formula 4, ##EQU1## in which L is the radical A as defined herein, R³, R⁴ and n are as defined herein, R⁷ is hydrogen and R² is respectively hydrogen or lower alkyl; treating the last-named compound with dihydropyran in the presence of an acid to obtain the corresponding compound of formula 4 in which L is the said radical A, R², R³, R⁴ and n are as defined herein and R⁷ is tetrahydropyran-2-yl; followed by treating the instant compound of formula 4 with an approximately equimolar amount a malonic ester derivative of formula 5, ##EQU2## in which R¹ and R⁸ each are lower alkyl and Z and m are as defined herein, at a temperature of 80° -150° C for 30 minutes to six hours, in the presence of a base selected from the group consisting of alkali metal alkoxides and sodium hydride whereby the compounds of formula 4 and 5 undergo a base catalyzed condensation to give the corresponding cyclopentanonetriester of formula 6, ##SPC12## in which m, n, Z, R², R³ R⁴, R⁵ and R⁸ are as defined hereinbefore, R¹ is lower alkyl and R⁷ is hydrogen or tetrahydropyran-2-yl; followed, when R⁷ is tetrahydropyran-2-yl, by treating the last-named cyclopentanonetriester of formula 6 with an acid in an inert solvent in the presence of water to obtain the corresponding compound of formula 6 in which R⁷ is hydrogen; and treating the instant compound of formula 6 with an alkali metal hydroxide in the presence of water to give the corresponding compound of formula 1 in which m, n, Z, R², R³ and R⁴, are as defined herein, X and Y together are oxo and R¹ is hydrogen; thereafter, when R¹ in formula 1 is lower alkyl, treating the last-named compound with a lower alkanol containing one to three carbon atoms in the presence of an acid catalyst to obtain its corresponding ester derivative of formula 1 in which m, n, Z, R², R³ and R⁴ are as defined herein, X and Y together are oxo and R is lower alkyl; and, when X is hydroxy and Y is hydrogen, treating the last-named compound of formula 1 in which R¹ is hydrogen or lower alkyl with a complex borohydride to obtain the corresponding compound of formula 1 in which m, n, Z, R², R³, R⁴ are as defined herein X is hydroxy, Y is hydrogen and R¹ is hydrogen or lower alkyl. 